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Background: Interleukin-33 is a member of the IL-1 cytokine family whose functions are mediated and modulated by the ST2 receptor. IL-33-ST2 expression and interactions have been explored in mouse macrophages but little is known about the effect of IL-33 on human macrophages. The expression of ST2 transcript and protein levels, and IL-33-mediated effects on M1 (i.e. classical activation) and M2 (i.e. alternative activation) chemokine marker expression in human bone marrow-derived macrophages were examined. Results: Human macrophages constitutively expressed the membrane-associated (i.e. ST2L) and the soluble (i.e. sST2) ST2 receptors. M2 (IL-4 + IL-13) skewing stimuli markedly increased the expression of ST2L, but neither polarizing cytokine treatment promoted the release of sST2 from these cells. When added to naïve macrophages alone, IL-33 directly enhanced the expression of CCL3. In combination with LPS, IL-33 blocked the expression of the M2 chemokine marker CCL18, but did not alter CCL3 expression in these naive cells. The addition of IL-33 to M1 macrophages markedly increased the expression of CCL18 above that detected in untreated M1 macrophages. Similarly, alternatively activated human macrophages treated with IL-33 exhibited enhanced expression of CCL18 and the M2 marker mannose receptor above that detected in M2 macrophages alone. Conclusions: Together, these data suggest that primary responses to IL-33 in bone marrow derived human macrophages favors M1 chemokine generation while its addition to polarized human macrophages promotes or amplifies M2 chemokine expression. [ABSTRACT FROM AUTHOR]

Background: C-C chemokine receptor (CCR)7 is a regulator of dendritic cell and T cell migration, and its role in tissue wound healing has been investigated in various disease models. We have previously demonstrated that CCR7 and its ligand, chemokine (C-C motif) ligand (CCL)21, modulates wound repair in pulmonary fibrosis (PF) but the mechanism of this is unknown. The objective of this study was to investigate whether the absence of CCR7 protects against bleomycin (BLM)-induced PF. CCR7-/- mice failed to mount a fibrotic pulmonary response as assessed by histologic collagen staining and quantification by hydroxyproline. We hypothesized that the prominent characteristics of CCR7-/- mice, including elevated levels of cytokine and chemokine mediators and the presence of bronchus-associated lymphoid tissue (BALT) might be relevant to the protective phenotype. Results: Pulmonary fibrosis was induced in CCR7+/+ and CCR7-/- mice via a single intratracheal injection of BLM. We found that the lung cytokine/chemokine milieu associated with the absence of CCR7 correlated with an increase in BALT, and might be attributable to regulatory T cell (Treg) homeostasis and trafficking within the lungs and lymph nodes. In response to BLM challenge, CCR7-/- mice exhibited an early, steady increase in lung CD4+ T cells and increased CD4+ CD25+ FoxP3+ Tregs in the lungs 21 days after challenge. These findings are consistent with increased lung expression of interleukin-2 and indoleamine 2,3-dioxygenase in CCR7-/- mice, which promote Treg expansion. Conclusions: Our study demonstrates that the protective phenotype associated with BLM-treated CCR7-/- mice correlates with the presence of BALT and the anchoring of Tregs in the lungs of CCR7-/- mice. These data provide novel evidence to support the further investigation of CCR7-mediated Treg trafficking in the modulation of BLMinduced PF. [ABSTRACT FROM AUTHOR]

Acute exacerbations by infectious agents contribute to the high mortality rate associated with IPF. We and others have demonstrated that TLR expression in fibrosis is immunoregulatory via modulation of inflammatory events leading to fibrosis. Polarization of macrophages into M1 and M2 phenotype is determined by the Th1 and Th2 signals, where PF is promoted by a Th2-mediated microenvironment. We have previously reported that the lack of CCR4 is associated with a significant attenuation of PF. We have demonstrated that its ligand, CCL17, functions as profibrotic mediator by modulating macrophage polarization following bleomycin (BLM) challenge, and promotes an M1 to an M2 macrophage phenotype switch. The objective of this study was to investigate the roles of TLRs in the CCR4-/- mouse, and test whether the lack of CCR4 protects against fibrosis induced by a TLR challenge. We observed that macrophages from CCR4-/- mice express higher levels of TLR9 compared to WT (CCR4+/+) mice, and that CpG stimulation induced the expression of NOS2 (an M1 marker). A single intranasal CpG challenge administered 7 days post BLM reverses the protective effect associated with the absence of CCR4. Conversely, WT mice demonstrated a significant recovery from the fatal effects of BLM. These results suggest that CCR4 and TLR9 pathways cooperate in regulating macrophage activation during the development and exacerbation model of PF. [ABSTRACT FROM AUTHOR]