Kinase inhibition in autoimmunity and inflammation Zarrin, Ali A; Bao, Katherine; Lupardus, Patrick ...
Nature reviews. Drug discover/Nature reviews. Drug discovery,
01/2021, Letnik:
20, Številka:
1
Journal Article
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Despite recent advances in the treatment of autoimmune and inflammatory diseases, unmet medical needs in some areas still exist. One of the main therapeutic approaches to alleviate dysregulated ...inflammation has been to target the activity of kinases that regulate production of inflammatory mediators. Small-molecule kinase inhibitors have the potential for broad efficacy, convenience and tissue penetrance, and thus often offer important advantages over biologics. However, designing kinase inhibitors with target selectivity and minimal off-target effects can be challenging. Nevertheless, immense progress has been made in advancing kinase inhibitors with desirable drug-like properties into the clinic, including inhibitors of JAKs, IRAK4, RIPKs, BTK, SYK and TPL2. This Review will address the latest discoveries around kinase inhibitors with an emphasis on clinically validated autoimmunity and inflammatory pathways.
IgE not only provides protective immunity against helminth parasites but can also mediate the type I hypersensitivity reactions that contribute to the pathogenesis of allergic diseases such as ...asthma, allergic rhinitis and atopic dermatitis. Despite the importance of IgE in immune biology and allergic pathogenesis, the cells and the pathways that produce and regulate IgE are poorly understood. In this Review, we summarize recent advances in our understanding of the production and the regulation of IgE in vivo, as revealed by studies in mice, and we discuss how these findings compare to what is known about human IgE biology.
Microglia are specialized brain macrophages that play numerous roles in tissue homeostasis and response to injury. Colony stimulating factor 1 receptor (CSF1R) is a receptor tyrosine kinase required ...for the development, maintenance, and proliferation of microglia. Here we show that in adult mice peripheral dosing of function-blocking antibodies to the two known ligands of CSF1R, CSF1, and IL-34, can deplete microglia differentially in white and gray matter regions of the brain, respectively. The regional patterns of depletion correspond to the differential expression of CSF1 and IL-34. In addition, we show that while CSF1 is required to establish microglia in the developing embryo, both CSF1 and IL-34 are required beginning in early postnatal development. These results not only clarify the roles of CSF1 and IL-34 in microglia maintenance, but also suggest that signaling through these two ligands might support distinct sub-populations of microglia, an insight that may impact drug development for neurodegenerative and other diseases.
Paired Immunoglobulin-like Type 2 Receptor Alpha (PILRA) is a cell surface inhibitory receptor that recognizes specific O-glycosylated proteins and is expressed on various innate immune cell types ...including microglia. We show here that a common missense variant (G78R, rs1859788) of PILRA is the likely causal allele for the confirmed Alzheimer's disease risk locus at 7q21 (rs1476679). The G78R variant alters the interaction of residues essential for sialic acid engagement, resulting in >50% reduced binding for several PILRA ligands including a novel ligand, complement component 4A, and herpes simplex virus 1 (HSV-1) glycoprotein B. PILRA is an entry receptor for HSV-1 via glycoprotein B, and macrophages derived from R78 homozygous donors showed significantly decreased levels of HSV-1 infection at several multiplicities of infection compared to homozygous G78 macrophages. We propose that PILRA G78R protects individuals from Alzheimer's disease risk via reduced inhibitory signaling in microglia and reduced microglial infection during HSV-1 recurrence.
TPL2 kinase action and control of inflammation Xu, Daqi; Matsumoto, Marissa L.; McKenzie, Brent S. ...
Pharmacological research,
March 2018, 2018-03-00, 20180301, Letnik:
129
Journal Article
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Tumor progression locus 2 (TPL2, also known as COT or MAP3K8) is a mitogen-activated protein kinase kinase (MAP3K) activated downstream of TNFαR, IL1R, TLR, CD40, IL17R, and some ...GPCRs. TPL2 regulates the MEK1/2 and ERK1/2 pathways to regulate a cascade of inflammatory responses. In parallel to this, TPL2 also activates p38α and p38δ to drive the production of various inflammatory mediators in neutrophils. We discuss the implications of this finding in the context of various inflammatory diseases.
Immunoglobulin variable region exons are assembled in developing B cells by V(D)J recombination. Once mature, these cells undergo class-switch recombination (CSR) when activated by antigen. CSR ...changes the heavy chain constant region exons (Ch) expressed with a given variable region exon from C to a downstream Ch (for example, C , C or C ), thereby switching expression from IgM to IgG, IgE or IgA. Both V(D)J recombination and CSR involve the introduction of DNA double-strand breaks and their repair by means of end joining. For CSR, double-strand breaks are introduced into switch regions that flank C and a downstream Ch, followed by fusion of the broken switch regions. In mammalian cells, the 'classical' non-homologous end joining (C-NHEJ) pathway repairs both general DNA double-strand breaks and programmed double-strand breaks generated by V(D)J recombination. C-NHEJ, as observed during V(D)J recombination, joins ends that lack homology to form 'direct' joins, and also joins ends with several base-pair homologies to form microhomology joins. CSR joins also display direct and microhomology joins, and CSR has been suggested to use C-NHEJ. Xrcc4 and DNA ligase IV (Lig4), which cooperatively catalyse the ligation step of C-NHEJ, are the most specific C-NHEJ factors; they are absolutely required for V(D)J recombination and have no known functions other than C-NHEJ. Here we assess whether C-NHEJ is also critical for CSR by assaying CSR in Xrcc4- or Lig4-deficient mouse B cells. C-NHEJ indeed catalyses CSR joins, because C-NHEJ-deficient B cells had decreased CSR and substantial levels of IgH locus (immunoglobulin heavy chain, encoded by Igh) chromosomal breaks. However, an alternative end-joining pathway, which is markedly biased towards microhomology joins, supports CSR at unexpectedly robust levels in C-NHEJ-deficient B cells. In the absence of C-NHEJ, this alternative end-joining pathway also frequently joins Igh locus breaks to other chromosomes to generate translocations.
From humans to frogs, immunoglobulin class switching introduces different effector functions to antibodies through an intrachromosomal DNA recombination process at the heavy-chain locus. Although ...there are two conventional antibody classes (IgM, IgW) in sharks, their heavy chains are encoded by 20 to >100 miniloci. These representatives of the earliest jawed vertebrates possess a primordial immunoglobulin gene organization where each gene cluster is autonomous and contains a few rearranging gene segments (VH-D1-D2-JH) with one constant region, μ or ω.
V(D)J rearrangement always takes place within the μ cluster, but here we show that the VDJ can be expressed with constant regions from different clusters, although IgH genes are spatially distant, at >120 kb. Moreover, reciprocal exchanges take place between Igω and Igμ genes. Switching is augmented with deliberate immunization and is concomitant with somatic hypermutation activity. Because switching occurs independently of the partners' linkage position, some events involve transchromosomal recombination. The switch sites consist of direct joins between two genes in the 3′ intron flanking JH.
Our data are consistent with a mechanism of cutting or joining of distal DNA lesions initiated by activation-induced cytidine deaminase (AID), in the absence of mammalian-type switch regions. We suggest that, in shark, with its many autonomous IgH targeted by programmed DNA breakage, factors predisposing broken DNA ends to translocate configured the earliest version of class switch recombination.
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► Switching in sharks consistent with immunization and cytidine deaminase expression ► Isotype switching can be reciprocal between genes of established positions ► Switch joints show DNA double-strand breakage repaired by nonhomologous end-joining ► Unlike in tetrapods, switching in shark is bidirection between IgM and IgW
The actions of the immune system are finely tuned, involving complex communication and coordination between diverse immune and non-immune cells across the tissues of the body. A healthy immune system ...requires a precise balance between immunity and tolerance. Regulatory T cells (Tregs) have long been appreciated as one of the master regulators of this balance; their importance is underscored by the autoimmunity that develops in mice and humans when Tregs are missing or dysfunctional. In addition to the immunoregulatory roles of Tregs in suppressing autoimmunity and inflammation via control of adaptive and innate immune responses, several non-immune modulatory functions of Tregs have been identified in recent years. In this review, we have highlighted the growing literature on the action of Tregs in metabolism, stem cell maintenance, tissue repair, and angiogenesis. Alongside Tregs' immune suppressive role, these non-suppressive activities comprise a key function of Tregs in regulating health and disease. As Tregs receive increasing attention as therapeutic targets, understanding their non-canonical functions may become an important feature of Treg-directed interventions.
Tumor progression locus 2 (Tpl2, gene name MAP3K8), a mitogen-activated protein kinase, is widely expressed in immune and non-immune cells to integrate tumor necrosis factor (TNF), toll-like ...receptors (TLRs), and interleukin-1 (IL1) receptor signaling to regulate inflammatory response. Given its central role in inflammatory response, Tpl2 is an attractive small molecule drug target. However, the role of Tpl2 as an oncogene or tumor suppressor gene remains controversial, and its function outside immune cells is not understood. We therefore utilized a Tpl2 kinase dead (Tpl2-KD) mouse model in an 18-month aging study to further elucidate Tpl2 effects on lifespan and chronic disease. Histopathological studies revealed the incidence and severity of spontaneous tumors and non-neoplastic lesions were comparable between wild type and Tpl2-KD mice. The only finding was that male Tpl2-KD mice had higher bodyweight and an increased incidence of liver steatosis, suggesting a sex-specific role for Tpl2 in hepatic lipid metabolism. In conclusion, loss of Tpl2 kinase activity did not lead to increased tumorigenesis over aging in mice but affected likely alterations in lipid metabolism in male animals.
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•Comparable aging related tumor incidence observed in Tpl2-KD and WT mice.•Tumor incidence suggests lack of Tpl2 activity has no impact on tumorigenesis.•Tpl2 inhibitor did not cause cell hyperproliferation in vitro.•Aged male Tpl2-KD mice had increased bodyweight and liver steatosis compared to WT.•All other non-neoplastic age-related changes in Tpl2-KD and WT mice were comparable.
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