MSMP

MSMP (PSMP) is a secreted microprotein that functions as a chemokine-like ligand for the receptor CCR2, coupling epithelial damage signals to monocyte/macrophage recruitment and inflammatory tissue injury (PMID:31813573, PMID:28698550). In intestinal and hepatic disease, MSMP is induced in epithelial cells by inflammatory stimuli such as LPS and muramyl dipeptide, and acts through CCR2 to chemo-attract Ly6C-hi inflammatory monocytes, drive M1 macrophage polarization, and amplify proinflammatory cytokine output; in the liver this CCR2-dependent macrophage influx further activates hepatic stellate cells to produce fibrosis, and PSMP neutralization or genetic deletion blunts colitis and CCl4-induced liver injury (PMID:31813573, PMID:28698550). Independently, MSMP is secreted by cancer cells under hypoxia—through loss of CTCF binding at its enhancer following histone acetylation—and acts on endothelial cells to trigger MAPK signaling and tube formation, mediating resistance to anti-VEGF therapy (PMID:29059175). The receptor mediating MSMP's endothelial MAPK signaling has not been identified in the available corpus.

1. 2017 High

   Established MSMP/PSMP as a functional CCR2 ligand whose epithelial induction drives monocyte-dependent inflammation, defining its core chemoattractant role.

   Evidence In situ chemotaxis and adoptive transfer in a DSS colitis model, plus colonic overexpression and neutralizing antibody blockade

   PMID:28698550

   Open questions at the time

   • Did not resolve structural basis of MSMP-CCR2 binding
   • Did not establish whether MSMP acts in human inflammatory disease
2. 2017 Medium

   Identified a separate, hypoxia-driven secretion of MSMP by tumor cells that promotes angiogenesis and anti-VEGF resistance, expanding its role beyond immune chemoattraction.

   Evidence Genomic analysis of anti-VEGF-resistant tumors, CTCF ChIP, endothelial tube-formation assays, and in vivo siRNA knockdown via DOPC nanoliposomes

   PMID:29059175

   Open questions at the time

   • The endothelial receptor mediating MSMP-induced MAPK signaling was not identified
   • Whether CCR2 is involved in the endothelial/angiogenic effect was not tested
3. 2019 High

   Demonstrated through reciprocal genetic rescue that MSMP drives hepatic fibrosis via CCR2-dependent macrophage recruitment and stellate cell activation, solidifying its causal role in fibrotic disease.

   Evidence Psmp knockout mice with AAV8 human PSMP re-expression rescue, M1 polarization and LX-2 stellate cell assays, and neutralizing antibody (3D5) treatment across murine fibrosis models

   PMID:31813573

   Open questions at the time

   • Did not determine whether stellate cell activation is direct or secondary to macrophage recruitment
   • No structural characterization of the MSMP-CCR2 interaction

• The receptor and signaling pathway mediating MSMP's CCR2-independent endothelial/angiogenic activity remain undefined.
• Endothelial MSMP receptor unknown
• Relationship between the CCR2-dependent inflammatory axis and the angiogenic axis unresolved