Over half of breast-cancer-related deaths are due to recurrence 5 or more years after initial diagnosis and treatment. This latency suggests that a population of residual tumor cells can survive treatment and persist in a dormant state for many years. The role of the microenvironment in regulating the survival and proliferation of residual cells following therapy remains unexplored. Using a conditional mouse model for Her2-driven breast cancer, we identify interactions between residual tumor cells and their microenvironment as critical for promoting tumor recurrence. Her2 downregulation leads to an inflammatory program driven by TNFα/NFκB signaling, which promotes immune cell infiltration in regressing and residual tumors. The cytokine CCL5 is elevated following Her2 downregulation and remains high in residual tumors. CCL5 promotes tumor recurrence by recruiting CCR5-expressing macrophages, which may contribute to collagen deposition in residual tumors. Blocking this TNFα-CCL5-macrophage axis may be efficacious in preventing breast cancer recurrence.

/pdf/ccl5-promotes-breast-cancer-recurrence-through-macrophage-42yvdnd0x3.pdf

CCL5 promotes breast cancer recurrence through macrophage recruitment in residual tumors

Despite the diverse etiologies of drug-induced liver injury (DILI), innate immunity activation is a common feature involved in DILI progression. However, the involvement of innate immunity regulation in inflammation resolution and liver regeneration in DILI remains obscure. Herein, we identified the chemokine CCL5 as a central mediator of innate immunity regulation in the pathogenesis of DILI. First, we showed that serum and hepatic CCL5 levels are elevated in both DILI patients and an APAP-induced liver injury (AILI) mouse model. Interestingly, both nonparenchymal cells and stressed hepatocytes are cell sources of CCL5 induction in response to liver injury. Functional experiments showed that CCL5 deficiency has no effect on the early phase of AILI but promotes liver repair in the late phase mainly by promoting inflammation resolution and liver regeneration, which are associated with an increased number of hepatic M2 macrophages. Mechanistically, CCL5 can directly activate M1 polarization and impede M2 polarization through the CCR1- and CCR5-mediated activation of the MAPK and NF-κB pathways. We then showed that CCL5 inhibition mediated by either a CCL5-neutralizing antibody or the antagonist Met-CCL5 can greatly alleviate liver injury and improve survival in an AILI mouse model. Our data demonstrate CCL5 induction during DILI, identify CCL5 as a novel innate immunity regulator in macrophage polarization, and suggest that CCL5 blockage is a promising therapeutic strategy for the treatment of DILI.

/pdf/ccl5-deficiency-promotes-liver-repair-by-improving-2ql1qwuo4a.pdf

CCL5 deficiency promotes liver repair by improving inflammation resolution and liver regeneration through M2 macrophage polarization.

Astrocytes act as immune effector cells with the ability to produce a wide array of chemokines and cytokines in response to various stimuli. Macrophage migration inhibitory factor (MIF) is inducibly expressed in injured spinal cord contributing to excessive inflammation that affects motor functional recovery. Unknown is whether MIF can facilitate inflammatory responses through stimulating release of chemokines from astrocytes following spinal cord injury. Following the establishment of the contusion spinal cord injury rat model, the correlation of chemokine (C-C motif) ligand 5 (CCL5) expression with that of MIF was assayed by Western blot, ELISA, and immunohistochemistry. Immunoprecipitation was used to detect MIF interaction with membrane CD74 receptor. Intracellular signal transduction of MIF/CD74 axis was analyzed by transcriptome sequencing of primary astrocytes and further validated by treatment of various inhibitors. The effects of CCL5 released by astrocytes on macrophage migration were performed by transwell migration assay. The post-injury locomotor functions were assessed using the Basso, Beattie, and Bresnahan (BBB) locomotor scale. The protein levels of chemokine CCL5/RANTES were remarkably increased in the astrocytes of rat injured spinal cord, in parallel with the expression of MIF. Treatment of MIF inhibitor 4-IPP in the lesion sites resulted in a significant decrease of CCL5 protein levels. In vitro study revealed MIF was capable of facilitating CCL5 production of astrocytes through interaction with CD74 membrane receptor, and knockdown of this receptor attenuated such effects. Production of CCL5 in astrocytes was significantly blocked by inhibitor of c-Jun N-terminal kinase, rather than by those of ERK and P38. Recombinant CCL5 protein was found to be more effective in promoting migration of M2- compared to M1-type macrophages. Collectively, these data reveal a novel function of MIF in regulation of CCL5 release from astrocytes, which in turn favors for recruitment of inflammatory cells to the injured site of the spinal cord, in association with activation of excessive inflammation.

/pdf/macrophage-migration-inhibitory-factor-facilitates-1wlpc9sbsz.pdf

Macrophage migration inhibitory factor facilitates production of CCL5 in astrocytes following rat spinal cord injury.

Immune cells of the monocyte/macrophage lineage are characterized by their diversity, plasticity, and variety of functions. Among them, macrophages play a central role in antiviral responses, tissue repair, and fibrosis. Macrophages can be reprogrammed by environmental cues, thus changing their phenotype during an antiviral immune response as the viral infection progresses. While M1-like macrophages are essential for the initial inflammatory responses, M2-like macrophages are critical for tissue repair after pathogen clearance. Numerous reports have evaluated the detrimental effects that coronaviruses, e.g., HCoV-229E, SARS-CoV, MERS-CoV, and SARS-CoV-2, have on the antiviral immune response and macrophage functions. In this review, we have addressed the breadth of macrophage phenotypes during the antiviral response and provided an overview of macrophage-coronavirus interactions. We also discussed therapeutic approaches to target macrophage-induced complications, currently under evaluation in clinical trials for coronavirus disease 2019 patients. Additionally, we have proposed alternative approaches that target macrophage recruitment, interferon signaling, cytokine storm, pulmonary fibrosis, and hypercoagulability.

/pdf/targeting-macrophages-as-a-therapeutic-option-in-coronavirus-1ba6w2jr4j.pdf

Targeting Macrophages as a Therapeutic Option in Coronavirus Disease 2019

2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside (THSG) attenuates human platelet aggregation, secretion and spreading in vitro.

CCL5/RANTES, a chemoattractant for myeloid cells, is induced by hepatic ischemia/reperfusion injury (IRI). The roles of CCL5 in hepatic IRI were carried out by means of CCL5 immunodepletion, antagonistic competition by Met-CCL5, and treatment with recombinant murine CCL5 (rmCCL5). Depletion or inhibition of CCL5 reduced severity of hepatic IRI, whereas rmCCL5 treatment aggravated liver IRI as manifested in elevated serum alanine aminotransferase (ALT) and tissue myeloperoxidase (MPO) levels. Moreover, IRI severity was reduced in CCL5-knockout (CCL5-KO) mice versus wildtype (WT) mice, with drops in serum ALT level, intrahepatic MPO activity, and histological pathology. Bone marrow transplantion (BMT) studies show that myeloid cells and tissue cells are both required for CCL5-aggravated hepatic IRI. The profile of liver-infiltrating leukocyte subsets after hepatic reperfusion identified CD11b+ cells as the only compartment significantly reduced in CCL5-KO mice versus WT controls at early reperfusion phase. The role of CCL5 recruiting CD11b+ cells in early reperfusion was validated by in vitro transwell migration assay of murine primary macrophages (broadly characterized by their CD11b expression) in response to liver lysates after early reperfusion. Taken together, our results demonstrate a sequence of early events elicited by CCL5 chemoattracting macrophage that result in inflammatory aggravation of hepatic IRI.

/pdf/c-c-chemokine-ligand-5-is-critical-for-facilitating-59a8gwtz2k.pdf

C-C Chemokine Ligand-5 is critical for facilitating macrophage infiltration in the early phase of liver ischemia/reperfusion injury.

The anti-aggregation effects of ondansetron on platelets involve IP3 signaling and MAP kinase pathway, but not 5-HT3-dependent pathway

Preactivated and disaggregated shape-changed platelets, fixed shape-changed platelets, and a pharmaceutical composition thereof are used for treating acute and emergent inflammatory disease in a dosage of 1×106 to 1×108. Activated platelets release and transfer adhesion factors to the surface of platelet cells, and trap stromal vascularity inflammatory cells from inflammated and damaged place, and the stromal vascularity inflammatory cells are eliminated through the circulatory system to alleviate inflammation. The fixed shape-changed platelets are able to alleviate inflammation and sustainable for longer storage duration.

Polung Yang

Papers

C-C Chemokine Ligand-5 is critical for facilitating macrophage infiltration in the early phase of liver ischemia/reperfusion injury.

The anti-aggregation effects of ondansetron on platelets involve IP3 signaling and MAP kinase pathway, but not 5-HT3-dependent pathway

Application and pharmaceutical composition of preactivated and disaggregated shape-changed platelets