Objective-Interleukin(IL)-17A, an inflammatory cytokine, has been implicated in atherosclerosis, in which inflammatory cells within atherosclerotic plaques express IL-17A. However, its role in the development of atheroscelrosis remains to be controversial. Methods and Results-To directly examine the role of IL-17A in atherosclerosis, we generated apolipoprotein E (ApoE)/IL-17A double-deficient (ApoE

Immune responses must be well restrained in a steady state to avoid excessive inflammation. However, such restraints are quickly removed to exert anti-microbial responses. Here, we report a role of autophagy in an early host anti-fungal response by enhancing NFκB activity through A20 sequestration. Enhancement of NFκB activation is achieved by autophagic depletion of A20, an NFκB inhibitor, in F4/80hi macrophages in the spleen, peritoneum, and kidney. We show that p62, an autophagic adaptor protein, captures A20 to sequester it in the autophagosome. This allows the macrophages to release chemokines to recruit neutrophils. Indeed, mice lacking autophagy in myeloid cells show higher susceptibility to Candida albicans infection due to impairment in neutrophil recruitment. Thus, at least in the specific aforementioned tissues, autophagy appears to break A20-dependent suppression in F4/80hi macrophages, which express abundant A20 and contribute to the initiation of efficient innate immune responses.

Osteopontin is critically involved in rheumatoid arthritis; however, the molecular cross-talk between osteopontin and joint cell components that leads to the inflammatory joint destruction is largely unknown. We found that not only osteopontin but also tenascin-C and their common receptor, α9 integrin, are expressed at arthritic joints. The local production of osteopontin and tenascin-C is mainly due to synovial fibroblasts and, to a lesser extent, synovial macrophages. Synovial fibroblasts and macrophages express α9 integrin, and autocrine and paracrine interactions of α9 integrin on synovial fibroblasts and macrophages and its ligands contribute differently to the production of proinflammatory cytokines and chemokines. α9 integrin is also involved in the recruitment and accumulation of inflammatory cells. Inhibition of α9 integrin function with an anti-α9 integrin Ab significantly reduces the production of arthrogenic cytokines and chemokines and ameliorates ongoing arthritis. Thus, we identified α9 integrin as a critical intrinsic regulator that controls the development of autoimmune arthritis.

The interaction between matricellular proteins such as tenascin-C (TN-C) and osteopontin (OPN) and integrins has been implicated in the pathology of rheumatoid arthritis in which Th17 cells are recognized as primary pathogenic cells. The differentiation of Th17 cells is tightly regulated by cytokines derived from APCs, receiving various signals including TLR stimuli. In this study, we used a collagen-induced arthritis model and found that increased numbers of α9 integrin-positive conventional dendritic cells and macrophage were detectable in the draining lymph node (dLN) shortly following first immunization, and these cells produced both TN-C and OPN, ligands for α9 integrin. α9 integrin-mediated signaling, induced by TN-C and OPN, promoted the production of Th17-related cytokines by conventional dendritic cells and macrophages in synergy with TLR2 and 4 signaling. This led to the Th17 cell differentiation and arthritis development. Moreover, Th17 cells generated under blocking of α9 integrin-mediated signaling showed low level of CCR6 expression and impaired migration ability toward CCL20. Thus, we have identified α9 integrin-mediated signaling by TN-C and OPN as a novel intrinsic regulator of pathogenic Th17 cell generation that contributes to the development of rheumatoid arthritis.

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The balance between immune activation and suppression must be regulated to maintain immune homeostasis. Tissue macrophages (MΦs) constitute the major cellular subsets of APCs within the body; however, how and what types of resident MΦs are involved in the regulation of immune homeostasis in the peripheral lymphoid tissues are poorly understood. Splenic red pulp MΦ (RPMs) remove self-Ags, such as blood-borne particulates and aged erythrocytes, from the blood. Although many scattered T cells exist in the red pulp of the spleen, little attention has been given to how RPMs prevent harmful T cell immune responses against self-Ags. In this study, we found that murine splenic F4/80hiMac-1low MΦs residing in the red pulp showed different expression patterns of surface markers compared with F4/80+Mac-1hi monocytes/MΦs. Studies with purified cell populations demonstrated that F4/80hiMac-1low MΦs regulated CD4+ T cell responses by producing soluble suppressive factors, including TGF-β and IL-10. Moreover, F4/80hiMac-1low MΦs induced the differentiation of naive CD4+ T cells into functional Foxp3+ regulatory T cells. Additionally, we found that the differentiation of F4/80hiMac-1low MΦs was critically regulated by CSF-1, and in vitro-generated bone marrow-derived MΦs induced by CSF-1 suppressed CD4+ T cell responses and induced the generation of Foxp3+ regulatory T cells in vivo. These results suggested that splenic CSF-1–dependent F4/80hiMac-1low MΦs are a subpopulation of RPMs and regulate peripheral immune homeostasis.

The balance between myeloid and lymphoid populations must be well controlled. Here, we report that a protein, osteopontin (OPN), skews the balance between myeloid and lymphoid populations during pathogenic conditions, such as infection and autoimmunity. Importantly, two OPN isoforms exert distinct effects in shifting the balance through cell type-specific regulation of apoptosis. Intracellular OPN (iOPN) reduces population sizes of myeloid progenitors and myeloid cells, and secreted OPN (sOPN) increases population sizes of lymphoid cells. The total impact of OPN in skewing leukocyte population balance was observed as host sensitivity to early systemic Candida infection and T cell-mediated colitis. This study suggests novel detrimental roles of two OPN isoforms causing the imbalance of leukocyte populations.

Lung is constantly exposed to outer environment; thus, the lung must maintain a state of immune ignorance or tolerance not to over-respond to harmless environmental stimuli. How cells in the lung control immune responses under the environmental exposure is not fully understood. Here, we found that autophagy plays a critical role in the lung-specific immune regulation to prevent spontaneous inflammation. Autophagy in pulmonary myeloid cells plays a role not only in maintaining low burdens of environmental microbes in the lung, but also in lowering mitochondrial reactive oxygen species production and raising a threshold in responding to Toll-like receptor 4 (TLR4) ligands in alveolar macrophages. Based on the mechanisms, we also found that intranasal instillation of antibiotics or an inhibitor of reactive oxygen species was efficient to prevent spontaneous pulmonary inflammation. Thus, autophagy in myeloid cells, particularly in alveolar macrophages, is critical in inhibiting spontaneous pulmonary inflammation; but pulmonary inflammation caused by dysfunctional autophagy is pharmacologically prevented.