Inflammatory microenvironments play a key role in skeletal muscle regeneration. The infiltration of CD8 T cells into injured muscle has been reported. However, the role of CD8 T cells during skeletal muscle regeneration remains unclear. In this study, we used cardiotoxin-induced mouse skeletal muscle injury/regeneration model to investigate the role of CD8 T cells. Muscle regeneration was impaired and matrix deposit was increased in CD8α-deficient mice compared with wild-type (WT) mice whose CD8 T cells were infiltrated into damaged muscle after cardiotoxin injection. Adoptive transfer of CD8 T cells to CD8α-deficient mice improved muscle regeneration and inhibited matrix remodeling. Compared with WT mice, CD8α deficiency limited the recruitment of Gr1high macrophages (MPs) into muscle, resulting in the reduction of satellite cell number. The expression of MCP-1 (MCP-1/CCL2), which regulates the migration of Gr1high MPs, was reduced in CD8α-deficient mice compared with WT mice. Coculture CD8 T cells with MPs promoted MCP-1 secretion. The i.m. injection of MCP-1 markedly promoted the recruitment of Gr1high MPs and improved muscle regeneration in CD8α-deficient mice. We conclude that CD8 T cells are involved in skeletal muscle regeneration by regulating the secretion of MCP-1 to recruit Gr1high MPs, which facilitate myoblast proliferation.

IL-17A-producing T lymphocytes play a crucial role in inflammatory kidney diseases, but their role in renal fibrosis remains to be explored. Here, we demonstrated that up-regulation of IL-17A was associated with the development of obstructive kidney injury. The primary source of IL-17A production in obstructed kidneys was infiltrating γδ T lymphocytes and CD4(+) T cells. IL-17A-deficient mice were protected from myofibroblast activation and extracellular matrix deposition, leading to reduced kidney fibrosis in response to obstructive injury. Mechanistically, IL-17A deficiency suppressed the expression of the chemokine RANTES in infiltrated CD3(+) T cells and peritubular inflammation following renal obstruction. Administration of RANTES-neutralizing antibody significantly reduced the accumulation of T cells and macrophages, and of collagen deposition in obstructed kidneys. Taken together, our results indicate that IL-17A contributes significantly to the pathogenesis of renal fibrosis by regulating RANTES-mediated inflammatory cell infiltration.

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Chemokines modulate inflammatory responses that are prerequisites for kidney injury. The specific role of monocyte-associated CX3CR1 and its cognate ligand CX3CL1 in unilateral ureteral obstruction (UUO)–induced kidney injury remains unclear. In this study, we found that UUO caused a CCR2-dependent increase in numbers of Ly6Chi monocytes both in the blood and kidneys and of Ly6C−CX3CR1+ macrophages in the obstructed kidneys of mice. Using CX3CR1gfp/+ knockin mice, we observed a rapid conversion of infiltrating proinflammatory Ly6C+CX3CR11o monocytes/macrophages to anti-inflammatory Ly6C−CX3CR1hi macrophages. CX3CR1 deficiency affected neither monocyte trafficking nor macrophage differentiation in vivo upon renal obstruction, but CX3CR1 expression in monocytes and macrophages was required for increases in fibrosis in the obstructed kidneys. Mechanistically, CX3CL1–CX3CR1 interaction increases Ly6C−CX3CR1hi macrophage survival within the obstructed kidneys. Therefore, CX3CL1 and CX3CR1 may represent attractive therapeutic targets in obstructive nephropathy.