Type 2 immunity mediates protective responses to helminths and pathological responses to allergens, but it also has broad roles in the maintenance of tissue integrity, including wound repair. Type 2 ...cytokines are known to promote fibrosis, an overzealous repair response, but their contribution to healthy wound repair is less well understood. This review discusses the evidence that the canonical type 2 cytokines, IL-4 and IL-13, are integral to the tissue repair process through two main pathways. First, essential for the progression of effective tissue repair, IL-4 and IL-13 suppress the initial inflammatory response to injury. Second, these cytokines regulate how the extracellular matrix is modified, broken down, and rebuilt for effective repair. IL-4 and/or IL-13 amplifies multiple aspects of the tissue repair response, but many of these pathways are highly redundant and can be induced by other signals. Therefore, the exact contribution of IL-4Rα signaling remains difficult to unravel.
The cardinal features of adaptive immunity are memory and antigen-specificity. Since Th2 cells are part of the adaptive immune system, this raises the question of why we need to "remember" to repair ...the wounds that are induced by specific parasites. ...Th2 cytokines mediate rapid repair while also minimizing the number of incoming parasites via IgE or flushing out intestinal parasites via alterations to gut physiology and excess mucus production.
In many mammalian tissues, mature differentiated cells are replaced by self-renewing stem cells, either continuously during homeostasis or in response to challenge and injury. For example, ...hematopoietic stem cells generate all mature blood cells, including monocytes, which have long been thought to be the major source of tissue macrophages. Recently, however, major macrophage populations were found to be derived from embryonic progenitors and to renew independently of hematopoietic stem cells. This process may not require progenitors, as mature macrophages can proliferate in response to specific stimuli indefinitely and without transformation or loss of functional differentiation. These findings suggest that macrophages are mature differentiated cells that may have a self-renewal potential similar to that of stem cells.
The term ‘macrophage’ encompasses tissue cells that typically share dependence on the same transcriptional regulatory pathways (e.g. the transcription factor PU.1) and growth factors (e.g. ...CSF1/IL‐34). They share a core set of functions that largely arise from a uniquely high phagocytic capacity manifest in their ability to clear dying cells, pathogens and scavenge damaged, toxic or modified host molecules. However, macrophages demonstrate a remarkable degree of tissue‐specific functionality and have diverse origins that vary by tissue site and inflammation status. With our understanding of this diversity has come an appreciation of the longevity and replicative capacity of tissue‐resident macrophages and thus the realisation that macrophages may persist through tissue perturbations and inflammatory events with important consequences for cell function. Here, we discuss our current understanding of the parameters that regulate macrophage survival and function, focusing on the relative importance of the tissue environment versus cell‐intrinsic factors, such as origin, how long a cell has been resident within a tissue and prior history of activation. Thus, we reconsider the view of macrophages as wholly plastic cells and raise many unanswered questions about the relative importance of cell life‐history versus environment in macrophage programming and function.
Macrophage function depends upon survival, transcriptional identity, and epigenetic status, which are products of both environmental and cell‐intrinsic factors. Thus, the view of macrophages as wholly plastic cells must be reconsidered. This review raises unanswered questions about the relative importance of cell life‐history versus environment in macrophage programming and function.
For decades, immunologists have studied the role of circulating immune cells in host protection, with a more recent appreciation of immune cells resident within the tissue microenvironment and the ...intercommunication between nonhematopoietic cells and immune cells. However, the extracellular matrix (ECM), which comprises at least a third of tissue structures, remains relatively underexplored in immunology. Similarly, matrix biologists often overlook regulation of complex structural matrices by the immune system. We are only beginning to understand the scale at which ECM structures determine immune cell localization and function. Additionally, we need to better understand how immune cells dictate ECM complexity. This review aims to highlight the potential for biological discovery at the interface of immunology and matrix biology.
Highlights • Type 2 immunity is associated with both helminth infection and responses to injury. • Pathways involved in tissue repair and helminth immunity overlap. • The IL-4Rα is central to ...accelerating both repair and helminth control. • Adaptive immunity contributes to more rapid wound repair.
The vertebrate immune system has evolved in concert with a broad range of infectious agents, including ubiquitous helminth (worm) parasites. The constant pressure of helminth infections has been a ...powerful force in shaping not only how immunity is initiated and maintained, but also how the body self-regulates and controls untoward immune responses to minimize overall harm. In this Review, we discuss recent advances in defining the immune cell types and molecules that are mobilized in response to helminth infection. Finally, we more broadly consider how these immunological players are blended and regulated in order to accommodate persistent infection or to mount a vigorous protective response and achieve sterile immunity.
Summary
Macrophages have long been center stage in the host response to microbial infection, but only in the past 10–15 years has there been a growing appreciation for their role in helminth ...infection and the associated type 2 response. Through the actions of the IL‐4 receptor α (IL‐4Rα), type 2 cytokines result in the accumulation of macrophages with a distinctive activation phenotype. Although our knowledge of IL‐4Rα‐induced genes is growing rapidly, the specific functions of these macrophages have yet to be established in most disease settings. Understanding the interplay between IL‐4Rα‐activated macrophages and the other cellular players is confounded by the enormous transcriptional heterogeneity within the macrophage population and by their highly plastic nature. Another level of complexity is added by the new knowledge that tissue macrophages can be derived either from a resident prenatal population or from blood monocyte recruitment and that IL‐4 can increase macrophage numbers through proliferative expansion. Here, we review current knowledge on the contribution of macrophages to helminth killing and wound repair, with specific attention paid to distinct cellular origins and plasticity potential.
Activation of the immune response during injury is a critical early event that determines whether the outcome of tissue restoration is regeneration or replacement of the damaged tissue with a scar. ...The mechanisms by which immune signals control these fundamentally different regenerative pathways are largely unknown. We have demonstrated that, during skin repair in mice, interleukin-4 receptor α (IL-4Rα)-dependent macrophage activation controlled collagen fibril assembly and that this process was important for effective repair while having adverse pro-fibrotic effects. We identified Relm-α as one important player in the pathway from IL-4Rα signaling in macrophages to the induction of lysyl hydroxylase 2 (LH2), an enzyme that directs persistent pro-fibrotic collagen cross-links, in fibroblasts. Notably, Relm-β induced LH2 in human fibroblasts, and expression of both factors was increased in lipodermatosclerosis, a condition of excessive human skin fibrosis. Collectively, our findings provide mechanistic insights into the link between type 2 immunity and initiation of pro-fibrotic pathways.
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•Type 2 immune signals are critical for macrophage polarization in skin-wound healing•Myeloid-cell-restricted IL-4Rα signaling controls collagen fibril assembly•Macrophage-derived Relm-α controls LH2-mediated pro-fibrotic collagen cross-linking•Expression of human Relm-β and LH2 is increased in lipodermatosclerosis
Type 2 immunity is a key regulator of tissue regeneration, but detailed mechanisms are unknown. Eming and colleagues have identified Relm-α as a critical link between type 2 immune signaling in myeloid cells and the initiation of collagen-modifying pathways in fibroblasts that, although important for effective repair, simultaneously determine scar formation.
A defining feature of resident gut macrophages is their high replenishment rate from blood monocytes attributed to tonic commensal stimulation of this site. In contrast, almost all other tissues ...contain locally maintained macrophage populations, which coexist with monocyte-replenished cells at homeostasis. In this study, we identified three transcriptionally distinct mouse gut macrophage subsets that segregate based on expression of Tim-4 and CD4. Challenging current understanding, Tim-4
CD4
gut macrophages were found to be locally maintained, while Tim-4
CD4
macrophages had a slow turnover from blood monocytes; indeed, Tim-4
CD4
macrophages were the only subset with the high monocyte-replenishment rate currently attributed to gut macrophages. Moreover, all macrophage subpopulations required live microbiota to sustain their numbers, not only those derived from blood monocytes. These findings oppose the prevailing paradigm that all macrophages in the adult mouse gut rapidly turn over from monocytes in a microbiome-dependent manner; instead, these findings supplant it with a model of ontogenetic diversity where locally maintained subsets coexist with rapidly replaced monocyte-derived populations.
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