Biology subjects

Christoffersson, G.

Publications and source records attributed to Christoffersson, G..

4 recordsLinked to original sources

bioRxiv2026

A splenic reservoir of pro-angiogenic neutrophils supports blood flow recovery after peripheral tissue ischemia

Background: Neutrophils accumulate at sites of ischemic injury, where a distinct subset characterized by CD49d+CXCR4hiVEGFR1hi expression promotes angiogenesis and contributes to blood flow recovery. This study investigated the function, origin, and recruitment mechanisms of these pro-angiogenic neutrophils (PANs) in a murine model of hindlimb ischemia and explored whether a corresponding population responds to acute ischemia in humans. Methods: Using spectral flow cytometry and immunohistochemistry, PANs and classical neutrophils were characterized in ischemic gastrocnemius muscle following hindlimb ischemia in mice. Blood flow recovery was assessed by laser speckle flowmetry. To determine the origin and mobilization mechanisms of PANs, splenectomy, chemical sympathectomy with 6-hydroxydopamine (6-OHDA), and surgical splenic denervation were performed. Translational studies examined blood samples collected during elective abdominal aortic aneurysm repair to assess PAN mobilization following acute lower limb ischemia induced by aortic cross-clamping. Results: PANs rapidly accumulated in ischemic muscle through a CD49d-dependent mechanism, and blockade of CD49d impaired blood flow recovery. During homeostasis, PANs were maintained within a splenic reservoir and were rapidly released into circulation following ischemia. Splenectomy and disruption of splenic sympathetic signaling significantly reduced PAN recruitment to ischemic tissue and impaired functional recovery. Mobilization was driven by ischemia-induced sympathetic activation, which decreased CXCL12 levels in the splenic red pulp, disrupting CXCR4-mediated PAN retention. In humans, a phenotypically similar PAN population was identified in peripheral blood, which increased rapidly following lower limb ischemia during aortic cross-clamping. The speed of this response is consistent with release from an extramedullary reservoir, although its anatomical source remains unknown. Conclusion: These findings identify the spleen as a reservoir of pro-angiogenic neutrophils in mice and reveal a neuroimmune mechanism regulating their mobilization and recruitment after ischemic injury. The rapid appearance of PAN in human circulation after acute ischemia suggests that comparable extramedullary neutrophil reservoirs may also exist in humans.

immunology↗

bioRxiv2024

Loss of chromogranin A and catestatin affect pancreatic islet homeostasis, endocrine function, and neurotransmitters

Chromogranin A (CgA), a neuroendocrine pro-hormone, undergoes proteolytic cleavage to yield bioactive peptides, notably catestatin (CST) and pancreastatin (PST), which exert opposing effects on metabolic and inflammatory processes. Using CgA and CST knockout (KO) mice, this study investigated their roles in pancreatic endocrine function, morphology, neurotransmitter dynamics, and systemic glucose homeostasis. CST deficiency induced insulin resistance, altered islet architecture, and heightened catecholamine levels, whereas CgA-KO mice lacking both CST and PST exhibited improved insulin sensitivity due to absence of PST. CST suppressed gluconeogenesis and enhanced glucagon regulation, while PST promoted insulin resistance and glucose production. Spatial mass spectrometry revealed altered neurotransmitter and polyamine profiles in pancreatic islets, implicating disrupted nerve-immune-islet interactions. CSTs modulation of catecholaminergic and inflammatory pathways positions it as a key regulator in the neuro-immune-endocrine axis. These findings highlight the therapeutic potential of targeting CgA-derived peptides, especially CST, for managing diabetes and metabolic-inflammatory diseases through precise peptide-based interventions.

immunology↗

bioRxiv2020

The anti-inflammatory peptide Catestatin blocks chemotaxis

Increased levels of the anti-inflammatory peptide catestatin (CST), a cleavage product of the pro-hormone chromogranin A, correlates with less severe outcomes in hypertension, colitis and diabetes. However, it is unknown how CST reduces the infiltration of monocytes and macrophages in inflamed tissues. Here, we report that CST blocks leukocyte migration towards inflammatory chemokines. By in vitro and in vivo migration assays, we show that although CST itself is weakly chemotactic, it blocks migration of monocytes and granulocytes to inflammatory attracting factor CC-chemokine ligand 2 (CCL2) and macrophage inflammatory protein 2 (MIP-2). Moreover, it directs CX3CR1+ macrophages away from pancreatic islets. These findings support the emerging notion that CST is a key anti-inflammatory modulator.

cell biology↗

bioRxiv2020

Chromogranin A regulates gut permeability via the antagonistic actions of its proteolytic peptides

AimA leaky gut barrier has been implicated in the initiation and progression of a multitude of diseases, e.g., inflammatory bowel disease, irritable bowel syndrome, celiac disease, and colorectal cancers. Here we show how pro-hormone Chromogranin A (CgA), produced by the enteroendocrine cells, and Catestatin (CST: hCgA352-372), the most abundant CgA-derived proteolytic peptide, affect the gut barrier. MethodsColon tissues from region-specific CST-knockout (CST-KO) mice, CgA-knockout (CgA-KO) and WT mice were analyzed by immunohistochemistry, ultrastructural and flowcytometry studies. FITC-dextran assays were used to measure intestinal barrier function. Mice were supplemented with CST or CgA fragment pancreastatin (PST: CgA250-301). The microbial composition of cecum was determined. CgA and CST levels were measured in blood of IBD patients. ResultsCST-KO mice displayed (i) elongated tight, adherens junctions and desmosomes similar to IBD patients, and (ii) gut inflammation. Consistently, plasma FITC-dextran measurements showed increased intestinal paracellular permeability in the CST-knockout mice. This correlated with a higher ratio of Firmicutes to Bacteroidetes, a dysbiotic pattern commonly encountered in various diseases. Supplementation of CST-knockout mice with recombinant CST restored paracellular permeability and reversed inflammation, whereas CgA-knockout mice supplementation with CST and/or PST in CgA-KO mice showed that intestinal paracellular permeability is regulated by the antagonistic roles of these two peptides: CST reduces and PST increases permeability. ConclusionThe pro-hormone CgA regulates the intestinal paracellular permeability. CST is both necessary and sufficient to reduce permeability and primarily acts via antagonizing the effects of PST.

physiology↗