Efferocytosis in Retinoblastoma

Retinoblastoma has varied presentations. As age advances in retinoblastoma, the undifferentiated tumour is the common appearance. Apoptosis in retinoblastoma in an untreated case can give us a clue about the tumour biology. Efferocytosis in intraocular tumour is a new concept which was seen in an enucleated eyeball specimen in a 4-year-old boy. Effective efferocytosis can be conceptualized for new pharmacodynamics application for anti-cancer drugs. We present a rare case of retinoblastoma with efferocytosis in retinal pigment epithelium and interesting apoptotic changes.

Top Five Stories of the Cellular Landscape and Therapies of Atherosclerosis:Current Knowledge and Future Perspectives

Atherosclerosis(AS)is characterized by impairment and apoptosis of endothelial cells,continuous systemic and focal inflammation and dysfunction of vascular smooth muscle cells,which is documented as the traditional cellular paradigm.However,the mechanisms appear much more complicated than we thought since a bulk of studies on efferocytosis,transdifferentiation and novel cell death forms such as ferroptosis,pyroptosis,and extracellular trap were reported.Discovery of novel pathological cellular landscapes provides a large number of therapeutic targets.On the other side,the unsatisfactory therapeutic effects of current treatment with lipid-lowering drugs as the cornerstone also restricts the efforts to reduce global AS burden.Stem cell-or nanoparticle-based strategies spurred a lot of attention due to the attractive therapeutic effects and minimized adverse effects.Given the complexity of pathological changes of AS,attempts to develop an almighty medicine based on single mechanisms could be theoretically challenging.In this review,the top stories in the cellular landscapes during the initiation and progression of AS and the therapies were summarized in an integrated perspective to facilitate efforts to develop a multi-targets strategy and fill the gap between mechanism research and clinical translation.The future challenges and improvements were also discussed.

Coronary atherosclerosis:Significance of autophagic armour

Autophagy is a lysosomal degradation pathway of cellular components such as organelles and long-lived proteins.Though a protective role for autophagy has been established in various patho-physiologic conditions such as cancer,neurodegeneration,aging and heart failure,a growing body of evidence now reveals a protective role for autophagy in atherosclerosis,mainly by removing oxidatively damaged organelles and proteins and also by promoting cholesterol egress from the lipid-laden cells.Recent studies by Razani et al and Liao et al unravel novel pathways that might be involved in autophagic protection and in this commentary we highlight the importance of autophagy in atherosclerosis in the light of these two recent papers.

Radiation-based immunogenic vaccine combined with a macrophage“checkpoint inhibitor”for boosting innate and adaptive immunity against metastatic colon cancers

Immunogenic dying tumor cells hold promising prospects as cancer vaccines to activate systemic immunity against both primary and metastatic tumors.Especially,X-ray-induced dying tumor cells are rich in highly immunogenic tumor-associated antigens and self-generated dsDNA as potent adjuvants.However,we found that the X-ray induction process can result in the excessive exposure of phosphatidylserine in cancer vaccines,which can specifically bind with the MerTK receptor on macrophages,acting as a“checkpoint”to facilitate immune silence in the tumor microenvironment.Therefore,we developed a novel strategy combining X-ray-induced cancer vaccines with UNC2250,a macrophage MerTK“checkpoint inhibitor,”for treating peritoneal carcinomatosis in colon cancer.By incorporating UNC2250 into the treatment regimen,immunosuppressive efferocytosis of macrophages,which relies on MerTK-directed recognition of phosphatidylserine on vaccines,was effectively blocked.Consequently,the immune analysis revealed that this combination strategy promoted the maturation of dendritic cells and M1-like repolarization of macrophages,thereby simultaneously eliciting robust adaptive and innate immunity.This innovative approach utilizing X-ray-induced vaccines combined with a checkpoint inhibitor may provide valuable insights for developing effective cancer vaccines and immunotherapies targeting colon cancer.

Reprogramming of cancer-associated fibroblasts by apoptotic cancer cells inhibits lung metastasis via Notch1-WISP-1 signaling

The interplay between apoptotic cancer cells and the tumor microenvironment modulates cancer progression and metastasis.Cancer-associated fibroblasts(CAFs)play a crucial role in promoting these events through paracrine communication.Here,we demonstrate that conditioned medium(CM)from lung CAFs exposed to apoptotic cancer cells suppresses TGF-β1-induced migration and invasion of cancer cells and CAFs.Direct exposure of CAFs to apoptotic 344SQ cells(ApoSQ)inhibited CAF migration and invasion and the expression of CAF activation markers.Enhanced secretion of Wnt‐induced signaling protein 1(WISP-1)by CAFs exposed to ApoSQ was required for these antimigratory and anti-invasive effects.Pharmacological inhibition of Notch1 activation or siRNA-mediated Notch1 silencing prevented WISP-1 production by CAFs and reversed the antimigratory and anti-invasive effects.Enhanced expression of the Notch ligand delta-like protein 1 on the surface of ultraviolet-irradiated apoptotic lung cancer cells triggered Notch1-WISP-1 signaling.Phosphatidylserine receptor brain-specific angiogenesis inhibitor 1(BAI1)-Rac1 signaling,which facilitated efferocytosis by CAFs,participated in crosstalk with Notch1 signaling for optimal production of WISP-1.In addition,a single injection of ApoSQ enhanced WISP-1 production,suppressed the expression of CAF activation markers in isolated Thy1^(+)CAFs,and inhibited lung metastasis in syngeneic immunocompetent mice via Notch1 signaling.Treatment with CM from CAFs exposed to ApoSQ suppressed tumor growth and lung metastasis,whereas treatment with WISP-1-immunodepleted CM from CAFs exposed to ApoSQ reversed the antitumorigenic and antimetastatic effects.Therefore,treatment with CM from CAFs exposed to apoptotic lung cancer cells could be therapeutically applied to suppress CAF activation,thereby preventing cancer progression and metastasis.

Targeting macrophage autophagy for inflammation resolution and tissue repair in inflammatory bowel disease

Inflammatory bowel disease(IBD)is a chronic,non-specific,recurrent inflammatory disease,majorly affecting the gastrointestinal tract.Due to its unclear pathogenesis,the current therapeutic strategy for IBD is focused on symptoms alleviation.Autophagy is a lysosome-mediated catabolic process for maintaining cellular homeostasis.Genome-wide association studies and subsequent functional studies have highlighted the critical role of autophagy in IBD via a number of mechanisms,including modulating macrophage function.Macrophages are the gatekeepers of intestinal immune homeostasis,especially involved in regulating inflammation remission and tissue repair.Interestingly,many autophagic proteins and IBD-related genes have been revealed to regulate macrophage function,suggesting that macrophage autophagy is a potentially important process implicated in IBD regulation.Here,we have summarized current understanding of macrophage autophagy function in pathogen and apoptotic cell clearance,inflammation remission and tissue repair regulation in IBD,and discuss how this knowledge can be used as a strategy for IBD treatment.