The Spleen Promotes the Secretion of CCL2 and Supports an M1 Dominant Phenotype in Hepatic Macrophages During Liver Fibrosis

Abstract

Background/Aims: Liver fibrosis is a complex process of tissue remodeling in response to injury. Hepatic macrophages have been identified as a key player in this process. As the largest lymphoid organ in the body, the spleen exerts both local and systemic effects on immune cell response. Splenectomy can improve hepatic function during the treatment of liver cirrhosis. However, whether the spleen influences disease progression through the modulation of hepatic macrophages remains unclear. Methods: We examined ex vivo hepatic macrophage responses from splenectomized or sham operated rats and performed splenocyte adoptive transfer studies, in combination with in vivo CCL2 blockade, in splenectomized or sham operated rats. Results: We found that splenectomy reduced fibrosis severity and monocyte/ macrophage infiltration within the injured liver. Splenectomy also reduced secretion of the monocyte chemokine CCL2 by hepatic macrophages. Ex vivo, splenocytes, especially splenic macrophages, promoted CCL2 secretion via upregulation of SOCS3 signaling in hepatic macrophages. Migration of splenic monocytes in response to conditioned medium from hepatic macrophages was inhibited by the blockade of SOCS3–CCL2–CCR2 signaling. Splenectomy also attenuated the establishment of an M1-dominant hepatic macrophage phenotype whilst the adoptive transfer of splenocytes could partly reverse this effect and exacerbate fibrosis. However, CCL2 blockade following adoptive splenocyte transfer restored the protective effects of splenectomy. Conclusion: Our study demonstrates that splenic macrophages can promote hepatic macrophage secretion of CCL2, which in turn facilitates monocyte recruitment and the establishment of an M1-dominant hepatic macrophage phenotype, and thus increase the severity of liver fibrosis.

HMGB1‐associated necroptosis and Kupffer cells M1 polarization underlies remote liver injury induced by intestinal ischemia/reperfusion in rats

“…Moreover, we further performed the dual presence of CD45 (leukocytes common antigen) and CD68 (pan macrophage marker) in peripheral blood, which was followed by surface staining of CD86 (M1 marker) and CD163 (M2 marker). 64 We identified an M1-dominant macrophage phenotype after intestinal I/R, while an increased M2 phenotype were observed after HMGB1 neutralization treatment. Likewise, our results found that the number of infiltrating KCs (CD68 + cells) was significantly increased in remote liver injury after intestinal I/R challenge, and most were M1-type macrophages (CD68 + /iNOS + cells).…”

“…Moreover, we further performed the dual presence of CD45 (leukocytes common antigen) and CD68 (pan macrophage marker) in peripheral blood, which was followed by surface staining of CD86 (M1 marker) and CD163 (M2 marker) . We identified an M1‐dominant macrophage phenotype after intestinal I/R, while an increased M2 phenotype were observed after HMGB1 neutralization treatment.…”

Spirulina supplementation in a mouse model of diet-induced liver fibrosis reduced the pro-inflammatory response of splenocytes

“…Indeed, it has been suggested that splenic red pulp macrophages are a major source of TGF-β1 and that splenectomy decreased serum TGF-β levels significantly while reducing liver fibrosis (26) . Furthermore, it has been demonstrated that the spleen supports the infiltration of monocytes into the liver through the secretion of C-C motif chemokine ligand 2 and that splenectomy decreased the infiltration of monocytes to reduce liver fibrosis (35) . Therefore, the spleen likely contributes to the development of liver fibrosis via monocyte infiltration and cytokine secretion and that SP may attenuate this liver inflammation through affecting the spleen.…”

Liver Macrophages: Old Dogmas and New Insights

“…In addition, splenic macrophages were found to promote KC activation in fibrosis models, which in turn facilitates monocyte recruitment and the establishment of an inflammatory hepatic macrophage phenotype, suggesting that splenic macrophages may indirectly influence hepatic inflammation by the release of signaling mediators into the portal vein. (73,74)…”