Tubular damage following ischemic renal injury is often reversible, and tubular epithelial cell (TEC) proliferation is a hallmark of tubular repair. Macrophages have been implicated in tissue repair, and CSF-1, the principal macrophage growth factor, is expressed by TECs. We therefore tested the hypothesis that CSF-1 is central to tubular repair using an acute renal injury and repair model, ischemia/reperfusion (I/R). Mice injected with CSF-1 following I/R exhibited hastened healing, as evidenced by decreased tubular pathology, reduced fibrosis, and improved renal function. Notably, CSF-1 treatment increased TEC proliferation and reduced TEC apoptosis. Moreover, administration of a CSF-1 receptor-specific (CSF-1R-specific) antibody after I/R increased tubular pathology and fibrosis, suppressed TEC proliferation, and heightened TEC apoptosis. To determine the contribution of macrophages to CSF-1-dependent renal repair, we assessed the effect of CSF-1 on I/R in mice in which CD11b + cells were genetically ablated and determined that macrophages only partially accounted for CSF-1-dependent tubular repair. We found that TECs expressed the CSF-1R and that this receptor was upregulated and coexpressed with CSF-1 in TECs following renal injury in mice and humans. Furthermore, signaling via the CSF-1R stimulated proliferation and reduced apoptosis in human and mouse TECs. Taken together, these data suggest that CSF-1 mediates renal repair by both a macrophage-dependent mechanism and direct autocrine/paracrine action on TECs.

MRL/MpJ-Faslpr (MRL-Faslpr) mice develop a spontaneous T cell and macrophage-dependent autoimmune disease that shares features with human lupus. Interactions via the programmed death 1/programmed death ligand 1 (PD-1/PD-L1) pathway down-regulate immune responses and provide a negative regulatory checkpoint in mediating tolerance and autoimmune disease. Therefore, we tested the hypothesis that the PD-1/PD-L1 pathway suppresses lupus nephritis and the systemic illness in MRL-Faslpr mice. For this purpose, we compared kidney and systemic illness (lymph nodes, spleen, skin, lung, glands) in PD-L1 null (−/−) and PD-L1 intact (wild type, WT) MRL-Faslpr mice. Unexpectedly, PD-L1−/−;MRL-Faslpr mice died as a result of autoimmune myocarditis and pneumonitis before developing renal disease or the systemic illness. Dense infiltrates, consisting of macrophage and T cells (CD8+ > CD4+), were prominent throughout the heart (atria and ventricles) and localized specifically around vessels in the lung. In addition, once disease was evident, we detected heart specific autoantibodies in PD-L1−/−;MRL-Faslpr mice. This unique phenotype is dependent on MRL-specific background genes as PD-L1−/−;MRL+/+ mice lacking the Faslpr mutation developed autoimmune myocarditis and pneumonitis. Notably, the transfer of PD-L1−/−;MRL+/+ bone marrow cells induced myocarditis and pneumonitis in WT;MRL+/+ mice, despite a dramatic up-regulation of PD-L1 expression on endothelial cells in the heart and lung of WT;MRL+/+ mice. Taken together, we suggest that PD-L1 expression is central to autoimmune heart and lung disease in lupus-susceptible (MRL) mice.

The nature and anatomic location of the protective memory CD8+ T cell subset induced by intranasal vaccination remain poorly understood. We developed a vaccination model to assess the anatomic location of protective memory CD8+ T cells and their role in lower airway infections. Memory CD8+ T cells elicited by local intranasal, but not systemic vaccination with an engineered non-replicative CD8+ T cell-targeted antigen confer enhanced protection to a lethal respiratory viral challenge. This protection depends on a distinct CXCR3LO resident memory CD8+ T cell (Trm) population that preferentially localizes to the pulmonary interstitium. Interstitial Trm —by being positioned close to the mucosa where infection occurs—act before inflammation can recruit circulating memory CD8+ T cells into the lung tissue. This results in a local protective immune response as early as one day post-infection. Hence, vaccine strategies that induce lung interstitial Trm may confer better protection against respiratory pathogens

Macrophages mediate kidney disease and are prominent in a mouse model (MRL-Fas lpr ) of lupus nephritis. Colony stimulating factor-1 (CSF-1) is the primary growth factor for macrophages, and CSF-1 deficiency protects MRL-Fas lpr mice from kidney disease and systemic illness. Whether this renoprotection derives from a reduction of macrophages and whether systemic CSF-1, as opposed to intrarenal CSF-1, promotes macrophage-dependent lupus nephritis remain unclear. Here, we found that increasing systemic CSF-1 hastened the onset of lupus nephritis in MRL-Fas lpr mice. Using mutant MRL-Fas lpr strains that express high, moderate, or no systemic CSF-1, we detected a much higher tempo of kidney disease in mice with the highest level of CSF-1. Furthermore, we uncovered a multistep CSF-1-dependent systemic mechanism central to lupus nephritis. CSF-1 heightened monocyte proliferation in the bone marrow (SSC low CD11b ϩ ), and these monocytes subsequently seeded the circulation. Systemic CSF-1 skewed the frequency of monocytes toward "inflammatory" (SSC low CD11b ϩ Ly6C high ) and activated populations that homed to sites of inflammation, resulting in a more rapid accumulation of intrarenal macrophages (CD11b ϩ CSF-1R ϩ or CD68 ϩ ) that induced apoptosis of tubular epithelial cells, damaging the kidney. In humans, we found increased levels of CSF-1 in the serum, urine, and kidneys of patients with lupus compared with healthy controls. Furthermore, serum and urine CSF-1 levels correlated with lupus activity, and intrarenal CSF-1 expression correlated with the histopathology activity index of lupus nephritis. Taken together, circulating CSF-1 is a potential therapeutic target for lupus nephritis.

Colony stimulating factor 1 (CSF-1), required for macrophage (Mø) survival, proliferation and activation, is upregulated in the tubular epithelial cells (TEC) during kidney inflammation. CSF-1 mediates Mø-dependent destruction in lupus-susceptible mice with nephritis and paradoxically, Mø-dependent renal repair in lupus-resistant mice after transient ischemia/reperfusion injury (I/R). We now report that I/R leads to defective renal repair, non-resolving inflammation and in turn, early-onset lupus nephritis in pre-clinical MRL-Faslpr mice. Moreover, defective renal repair is not unique to MRL-Faslpr mice as flawed healing is a feature of other lupus-susceptible mice (Sle 123) and MRL mice without the Faslpr mutation. Increasing CSF-1 hastens renal healing after I/R in lupus-resistant mice, but hinders healing, exacerbates non-resolving inflammation, and triggers more severe early-onset lupus nephritis in MRL-Faslpr mice. Probing further, the time-related balance of M1 “destroyer” Mø shifts towards the M2 “healer” phenotype in lupus-resistant mice after I/R, but M1 Mø continue to dominate in MRL-Faslpr mice. Moreover, hypoxic TEC release mediators, including CSF-1, that are responsible for stimulating the expansion of M1 Mø inherently poised to destroy the kidney in MRL-Faslpr mice. In conclusion, I/R induces CSF-1 in injured TEC that expands aberrant Mø (M1 phenotype) mediating defective renal repair and non-resolving inflammation, and thereby hasten the onset of lupus nephritis.