The Journal of immunology : official journal of the American Association of Immunologists
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Triggering receptor expressed on myeloid cells (TREM)-1 is an orphan receptor implicated in innate immune activation. Inhibition of TREM-1 reduces sepsis in mouse models, suggesting a role for it in immune responses triggered by bacteria. ⋯ Interestingly, multimerization of PGLYRP1 bypassed the need for peptidoglycan in TREM-1 activation, demonstrating that the PGLYRP1/TREM-1 axis can be activated in the absence of bacterial products. The role for PGLYRP1 as a TREM-1 activator provides a new mechanism by which bacteria can trigger myeloid cells, linking two known, but previously unrelated, pathways in innate immunity.
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Idiopathic pulmonary fibrosis is a devastating lung disease characterized by inflammation and the development of excessive extracellular matrix deposition. Currently, there are only limited therapeutic intervenes to offer patients diagnosed with pulmonary fibrosis. Although previous studies focused on structural cells in promoting fibrosis, our study assessed the contribution of macrophages. ⋯ Using an in vitro coculture system, macrophages isolated from in vivo bleomycin-challenged WT, but not IRAK-M(-/-), mice promoted increased collagen and α-smooth muscle actin expression from lung fibroblasts in an IL-13-dependent fashion. Finally, IRAK-M expression is upregulated in peripheral blood cells from idiopathic pulmonary fibrosis patients and correlated with markers of alternative macrophage activation. These data indicate expression of IRAK-M skews lung macrophages toward an alternatively activated profibrotic phenotype, which promotes collagen production, leading to the progression of experimental pulmonary fibrosis.
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Many of the biological properties of C5a are mediated through activation of its receptor (C5aR1), the expression of which has been demonstrated convincingly on myeloid cells, such as neutrophils, monocytes, and macrophages. In contrast, conflicting results exist regarding C5aR1 expression in dendritic cells (DCs) and lymphoid lineage cells. In this article, we report the generation of a floxed GFP-C5aR1 reporter knock-in mouse. ⋯ Mating the floxed GFP-C5aR1 mouse strain with LysMCre mice, we were able to specifically delete C5aR1 in neutrophils and macrophages, whereas C5aR1 expression was retained in DCs. In summary, our findings suggest that C5aR1 expression in mice is largely restricted to cells of the myeloid lineage. The novel floxed C5aR1 reporter knock-in mouse will prove useful to track C5aR1 expression in experimental models of acute and chronic inflammation and to conditionally delete C5aR1 in immune cells.
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The acute respiratory distress syndrome (ARDS) is a form of severe hypoxemic respiratory failure that is characterized by inflammatory injury to the alveolar capillary barrier, with extravasation of protein-rich edema fluid into the airspace. Although many modalities to treat ARDS have been investigated over the past several decades, supportive therapies remain the mainstay of treatment. In this article, we briefly review the definition, epidemiology, and pathophysiology of ARDS and present emerging aspects of ARDS pathophysiology that encompass modulators of the innate immune response, damage signals, and aberrant proteolysis that may serve as a foundation for future therapeutic targets.
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In multiple clinical conditions, including trauma and hemorrhage, reperfusion magnifies ischemic tissue damage. Ischemia induces expression of multiple neoantigens, including lipid alterations that are recognized by the serum protein, β2-glycoprotein I (β2-GPI). During reperfusion, binding of β2-GPI by naturally occurring Abs results in an excessive inflammatory response that may lead to death. ⋯ In addition, TLR2(-/-) mice also did not express other novel Ags, suggesting a sequential response. Unlike other TLRs, TLR2(-/-) mice lacked the appropriate Ab repertoire to induce intestinal IR tissue damage or inflammation. Together, these data suggest that, in addition to the inflammatory response, IR-induced injury requires TLR2 for naturally occurring Ab production.