Renal fibrosis is a major hallmark of chronic kidney disease that is considered to be a common end point of various types of renal disease. To date, the biological meaning of fibrosis during the ...progression of chronic kidney diseases is unknown and possibly depends on the cell type contributing to extracellular matrix production. During the past decade, the origin of myofibroblasts in the kidney has been intensively investigated. Determining the origins of renal myofibroblasts is important because these might account for the heterogeneous characteristics and behaviors of myofibroblasts. Current data strongly suggest that collagen-producing myofibroblasts in the kidney can be derived from various cellular sources. Resident renal fibroblasts and cells of hematopoietic origin migrating into the kidney seem to be the most important ancestors of myofibroblasts. It is likely that both cell types communicate with each other and also with other cell types in the kidney. In this review, we will discuss the current knowledge on the origin of scar-producing myofibroblasts and cellular events triggering fibrosis.
Inflammation and fibrosis Mack, Matthias
Matrix biology,
August 2018, 2018-08-00, 20180801, Letnik:
68-69
Journal Article
Recenzirano
Tissue damage and inflammation are important triggers for regeneration and fibrosis. Tissue damage not only induces inflammation in general, it also determines the type and polarization of ...inflammation by recruiting and activating a variety of different cells types of the innate and adaptive immune system. This review focuses on the pathways leading from tissue damage to inflammation, from inflammation to fibrosis and from fibrosis to function. It covers the pro- and antifibrotic properties of immunological mediators released from T cells, monocytes/macrophages, innate lymphoid cells, basophils and eosinophils and takes into account that extracellular matrix proteins are not only produced by mesenchymal fibroblasts but also by other cell types, especially infiltrating hematopoietic cells. The special requirements for activation and recruitment of these so called fibrocytes are described in detail.
•Covers the pathways from tissue damage to inflammation, from inflammation to fibrosis and from fibrosis to function•Covers the pro- and antifibrotic properties of immune cells and their mediators•Covers the special requirements for activation and recruitment of collagen-producing hematopoietic cells (fibrocytes)
During early embryogenesis, microglia arise from yolk sac progenitors that populate the developing central nervous system (CNS), but how the tissue-resident macrophages are maintained throughout the ...organism’s lifespan still remains unclear. Here, we describe a system that allows specific, conditional ablation of microglia in adult mice. We found that the microglial compartment was reconstituted within 1 week of depletion. Microglia repopulation relied on CNS-resident cells, independent from bone-marrow-derived precursors. During repopulation, microglia formed clusters of highly proliferative cells that migrated apart once steady state was achieved. Proliferating microglia expressed high amounts of the interleukin-1 receptor (IL-1R), and treatment with an IL-1R antagonist during the repopulation phase impaired microglia proliferation. Hence, microglia have the potential for efficient self-renewal without the contribution of peripheral myeloid cells, and IL-1R signaling participates in this restorative proliferation process.
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•Microglia repopulate within 5 days of depletion•Under defined host conditions, microglia can be replaced by BM cells•Without preconditioning, they renew themselves locally by massive proliferation•IL-1R1 on microglia is involved in self-renewal and maintenance
Microglia arise from yolk sac progenitors that populate the developing central nervous system (CNS), but how these cells are maintained in the adult remains unclear. Waisman and colleagues show via a genetic approach that after ablation, microglia repopulation is driven by local progenitors in response to IL-1R signaling.
Pathogenic human coronaviruses (CoVs), such as the severe acute respiratory syndrome (SARS)-CoV and the Middle East respiratory syndrome-CoV, cause acute respiratory illness. Epidemiological data ...from the 2002-2003 SARS epidemic and recent Middle East respiratory syndrome outbreak indicate that there may be sex-dependent differences in disease outcomes. To investigate these differences, we infected male and female mice of different age groups with SARS-CoV and analyzed their susceptibility to the infection. Our results showed that male mice were more susceptible to SARS-CoV infection compared with age-matched females. The degree of sex bias to SARS-CoV infection increased with advancing age, such that middle-aged mice showed much more pronounced differences compared with young mice. Enhanced susceptibility of male mice to SARS-CoV was associated with elevated virus titers, enhanced vascular leakage, and alveolar edema. These changes were accompanied by increased accumulation of inflammatory monocyte macrophages and neutrophils in the lungs of male mice, and depletion of inflammatory monocyte macrophages partially protected these mice from lethal SARS. Moreover, the sex-specific differences were independent of T and B cell responses. Furthermore, ovariectomy or treating female mice with an estrogen receptor antagonist increased mortality, indicating a protective effect for estrogen receptor signaling in mice infected with SARS-CoV. Together, these data suggest that sex differences in the susceptibility to SARS-CoV in mice parallel those observed in patients and also identify estrogen receptor signaling as critical for protection in females.
Wallerian degeneration (WD) is considered an essential preparatory stage to the process of axonal regeneration. In the peripheral nervous system, infiltrating monocyte-derived macrophages, which use ...the chemokine receptor CCR2 to gain entry to injured tissues from the bloodstream, are purportedly necessary for efficient WD. However, our laboratory has previously reported that myelin clearance in the injured sciatic nerve proceeds unhindered in the
mouse model. Here, we extensively characterize WD in male
mice and identify a compensatory mechanism of WD that is facilitated primarily by neutrophils. In response to the loss of CCR2, injured
sciatic nerves demonstrate prolonged expression of neutrophil chemokines, a concomitant extended increase in the accumulation of neutrophils in the nerve, and elevated phagocytosis by neutrophils. Neutrophil depletion substantially inhibits myelin clearance after nerve injury in both male WT and
mice, highlighting a novel role for these cells in peripheral nerve degeneration that spans genotypes.
The accepted view in the basic and clinical neurosciences is that the clearance of axonal and myelin debris after a nerve injury is directed primarily by inflammatory CCR2
macrophages. However, we demonstrate that this clearance is nearly identical in WT and
mice, and that neutrophils replace CCR2
macrophages as the primary phagocytic cell. We find that neutrophils play a major role in myelin clearance not only in
mice but also in WT mice, highlighting their necessity during nerve degeneration in the peripheral nervous system. These degeneration studies may propel improvements in nerve regeneration and draw critical parallels to mechanisms of nerve degeneration and regeneration in the CNS and in the context of peripheral neuropathies.
Highly pathogenic human respiratory coronaviruses cause acute lethal disease characterized by exuberant inflammatory responses and lung damage. However, the factors leading to lung pathology are not ...well understood. Using mice infected with SARS (severe acute respiratory syndrome)-CoV, we show that robust virus replication accompanied by delayed type I interferon (IFN-I) signaling orchestrates inflammatory responses and lung immunopathology with diminished survival. IFN-I remains detectable until after virus titers peak, but early IFN-I administration ameliorates immunopathology. This delayed IFN-I signaling promotes the accumulation of pathogenic inflammatory monocyte-macrophages (IMMs), resulting in elevated lung cytokine/chemokine levels, vascular leakage, and impaired virus-specific T cell responses. Genetic ablation of the IFN-αβ receptor (IFNAR) or IMM depletion protects mice from lethal infection, without affecting viral load. These results demonstrate that IFN-I and IMM promote lethal SARS-CoV infection and identify IFN-I and IMMs as potential therapeutic targets in patients infected with pathogenic coronavirus and perhaps other respiratory viruses.
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•SARS-CoV causes a lethal respiratory infection in BALB/c mice•Robust SARS-CoV replication and delayed IFN-I signaling promote disease•IFN-I induces influx of pathogenic inflammatory monocytes and vascular leakage•Disease severity is ameliorated in the absence of IFN signaling
Factors that lead to lethal disease following SARS-CoV infection are not well understood. Channappanavar et al. show that robust virus replication and delayed IFN-I signaling promote severe disease. IFN-I promotes accumulation of pathogenic monocyte-macrophages resulting in lung immunopathology, vascular leakage, and suboptimal T cell responses.
Radiotherapy induces and promotes innate and adaptive immunity in which host STING plays an important role. However, radioresistance in irradiated tumors can also develop, resulting in relapse. Here ...we report a mechanism by which extrinsic resistance develops after local ablative radiation that relies on the immunosuppressive action of STING. The STING/type I interferon pathway enhances suppressive inflammation in tumors by recruiting myeloid cells in part via the CCR2 pathway. Germ-line knockouts of CCR2 or treatment with an anti-CCR2 antibody results in blockade of radiation-induced MDSC infiltration. Treatment with anti-CCR2 antibody alleviates immunosuppression following activation of the STING pathway, enhancing the anti-tumor effects of STING agonists and radiotherapy. We propose that radiation-induced STING activation is immunosuppressive due to (monocytic) M-MDSC infiltration, which results in tumor radioresistance. Furthermore, the immunosuppressive effects of radiotherapy and STING agonists can be abrogated in humans by a translational strategy involving anti-CCR2 antibody treatment to improve radiotherapy.
Macrophages are highly heterogeneous tissue-resident immune cells that perform a variety of tissue-supportive functions. The current paradigm dictates that intestinal macrophages are continuously ...replaced by incoming monocytes that acquire a pro-inflammatory or tissue-protective signature. Here, we identify a self-maintaining population of macrophages that arise from both embryonic precursors and adult bone marrow-derived monocytes and persists throughout adulthood. Gene expression and imaging studies of self-maintaining macrophages revealed distinct transcriptional profiles that reflect their unique localization (i.e., closely positioned to blood vessels, submucosal and myenteric plexus, Paneth cells, and Peyer’s patches). Depletion of self-maintaining macrophages resulted in morphological abnormalities in the submucosal vasculature and loss of enteric neurons, leading to vascular leakage, impaired secretion, and reduced intestinal motility. These results provide critical insights in intestinal macrophage heterogeneity and demonstrate the strategic role of self-maintaining macrophages in gut homeostasis and intestinal physiology.
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•Self-maintaining macrophages (gMacs) colonize distinct niches of the gut•gMacs have a unique transcriptional profile depending on the niche in which they reside•gMacs support enteric neurons and submucosal vasculature•Loss of gMacs results in vascular leakage, reduced intestinal secretion, and transit
A population of self-maintaining macrophages that persists throughout adulthood promotes intestinal homeostasis, contrary to the idea that short-lived monocytes perform this function.
SARS-CoV-2 has caused the global COVID-19 pandemic. Although passively delivered neutralizing antibodies against SARS-CoV-2 show promise in clinical trials, their mechanism of action in vivo is ...incompletely understood. Here, we define correlates of protection of neutralizing human monoclonal antibodies (mAbs) in SARS-CoV-2-infected animals. Whereas Fc effector functions are dispensable when representative neutralizing mAbs are administered as prophylaxis, they are required for optimal protection as therapy. When given after infection, intact mAbs reduce SARS-CoV-2 burden and lung disease in mice and hamsters better than loss-of-function Fc variant mAbs. Fc engagement of neutralizing antibodies mitigates inflammation and improves respiratory mechanics, and transcriptional profiling suggests these phenotypes are associated with diminished innate immune signaling and preserved tissue repair. Immune cell depletions establish that neutralizing mAbs require monocytes and CD8+ T cells for optimal clinical and virological benefit. Thus, potently neutralizing mAbs utilize Fc effector functions during therapy to mitigate lung infection and disease.
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•Neutralizing mAbs do not require Fc effector functions when given as prophylaxis•MAbs against SARS-CoV-2 require Fc effector functions for therapeutic protection•Fc engagement of mAbs decreases viral burden and mitigates lung inflammation•CD8+ T cells and monocytes are necessary for optimal Fc-dependent mAb protection
Neutralizing human monoclonal antibodies (mAbs) against SARS-CoV-2 require Fc effector functions for optimal protection during post-exposure therapy, with intact mAbs reducing SARS-CoV-2 burden and lung disease in rodent models better than LALA-PG loss-of-function Fc variant mAbs and requiring monocytes and CD8+ T cells for optimal clinical and virological benefit.
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