CXCL4 and CXCL4L1 Differentially Affect Monocyte Survival and Dendritic Cell Differentiation and Phagocytosis

Abstract

Upon inflammation, circulating monocytes leave the bloodstream and migrate into the tissues, where they differentiate after exposure to various growth factors, cytokines or infectious agents. The best defined macrophage polarization types are M1 and M2. However, the platelet-derived CXC chemokine CXCL4 induces the polarization of macrophages into a unique phenotype. In this study, we compared the effect of CXCL4 and its variant CXCL4L1 on the differentiation of monocytes into macrophages and into immature monocyte-derived dendritic cells (iMDDC). Differently to M-CSF and CXCL4, CXCL4L1 is not a survival factor for monocytes. Moreover, the expression of the chemokine receptors CCR2, CCR5 and CXCR3 was significantly higher on CXCL4L1-treated monocytes compared to M-CSF- and CXCL4-stimulated monocytes. IL-1 receptor antagonist (IL-1RN) expression was upregulated by CXCL4 and downregulated by CXCL4L1, respectively, whereas both chemokines reduced the expression of the mannose receptor (MRC). Furthermore, through activation of CXCR3, CXCL4L1-stimulated monocytes released significantly higher amounts of CCL2 and CXCL8 compared to CXCL4-treated monocytes, indicating more pronounced inflammatory traits for CXCL4L1. In contrast, in CXCL4L1-treated monocytes, the production of CCL22 was lower. Compared to iMDDC generated in the presence of CXCL4L1, CXCL4-treated iMDDC showed an enhanced phagocytic capacity and downregulation of expression of certain surface markers (e.g. CD1a) and specific enzymes (e.g. MMP-9 and MMP-12). CXCL4 and CXCL4L1 did not affect the chemokine receptor expression on iMDDC and cytokine production (CCL2, CCL18, CCL22, CXCL8, IL-10) by CXCL4- or CXCL4L1-differentiated iMDDC was similar. We can conclude that both CXCL4 and CXCL4L1 exert a direct effect on monocytes and iMDDC. However, the resulting phenotypes are different, which suggests a unique role for the two CXCL4 variants in physiology and/or pathology.

CXCL4 is a novel inducer of human Th17 cells and correlates with IL‐17 and IL‐22 in psoriatic arthritis

“…3B), but not with pDCs or B cells. Previous data from others and our group indicate clear immunomodulatory effects of CXCL4 at higher doses [21,22]. In co-culture with monocytes, increasing amount of CXCL4 up to 5 μg/mL did not additionally enhance the IL-17 induction (Supporting Information Fig.…”

The prognostic significance of circulating serum amyloid A and CXC chemokine ligand 4 in osteosarcoma

“…For example, the release of pro-inflammatory cytokines, such as CXCL4, by activated platelets plays an important role in the activation of monocytes during acute vascular injury or chronic disease. 24 Hence, the prognostic values of SAA and CXCL4 in this study may be associated to their roles in tumor burden or inflammation. In the current study, we found that lower CXCL4 levels trended toward a poor outcome, which argues against its prognostic correlation being solely attributed to its role as an inflammation marker.…”

“…Similar to SAA, CXCL4 is also considered a positive acute‐phase reactant, indicating its level can increase during pro‐inflammatory conditions. For example, the release of pro‐inflammatory cytokines, such as CXCL4, by activated platelets plays an important role in the activation of monocytes during acute vascular injury or chronic disease …”

CXCL4L1 Promoter Polymorphisms Are Associated with Improved Renal Function in Type 1 Diabetes

“…Second, CXCL4L1 increase in NHMCs supernatant elevated the expression levels of two prominent inhibitors of kidney inflammation: Smad7 and IkBa. Human mesangial cells were previously shown to express CXCR3, which is the most investigated receptor of CXCL4L1 (21,33,34). Although CXCR3 signaling remains to be investigated in NHMCs, the activation of Smad7 and IkBa by CXCL4L1 was not markedly high in these cells or depending on phosphorylation of the TAK1 or IKK signaling pathways, which are known to induce Smad7 and IkBa highly and transiently (Supplemental Figs.…”

“…Despite the strong association between the CXCL4L1 gene and renal function in T1D, the function of mesangial cells may represent only a part of the protective effect of CXCL4L1 expression on renal function. Recently, CXCL4L1 has been shown to induce monocytes to differentiate into distinct macrophage phenotypes different from M1 and M2 in vitro (34). Thus, CXCL4L1 expression is also likely to affect the response of resident immune cells in the kidney.…”