Mathangi Janakiraman

All Publications

• Gpr37 modulates the severity of inflammation-induced GI dysmotility by regulating enteric reactive gliosis. iScience Robertson, K., Hahn, O., Tantry, A., Robinson, B. G., Faruk, A. T., Janakiraman, M., Namkoong, H., Kim, K., Ye, J., Bishop, E. S., Hall, R. A., Wyss-Coray, T., Becker, L., Kaltschmidt, J. A. 2025; 28 (7): 112885

  Abstract

  The enteric nervous system (ENS) is contained within two layers of the gut wall and is made up of neurons and enteric glial cells (EGCs) that regulate gastrointestinal (GI) function. EGCs in both inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) change in response to inflammation, referred to as reactive gliosis. Whether EGCs restricted to a specific layer or region within the GI tract alone can influence intestinal immune response is unknown. Using bulk RNA-sequencing and in situ hybridization, we identify G-protein coupled receptor Gpr37, as a gene expressed in EGCs of the myenteric plexus, one of the two layers of the ENS. We show that Gpr37 contributes to key components of LPS-induced reactive gliosis including activation of NF-kB and IFN-y signaling and response genes, lymphocyte recruitment, and inflammation-induced GI dysmotility. Targeting Gpr37 presents a potential avenue for modifying inflammatory processes in the ENS.

  View details for DOI 10.1016/j.isci.2025.112885

  View details for PubMedID 40678517

• Altered Bone Morphogenetic Protein 2 Signaling Causes Age-Dependent Decline in Gut Motility Independent of Muscularis Macrophages. Gastro hep advances Bishop, E. S., Morley, L., Janakiraman, M., Vikram, A., Namkoong, H., Becker, L. 2025; 4 (7): 100673

  View details for DOI 10.1016/j.gastha.2025.100673

  View details for PubMedID 40503185

  View details for PubMedCentralID PMC12158492

• An engineered Fc fusion protein that targets antigen-specific T cells and autoantibodies mitigates autoimmune disease. Journal of neuroinflammation Janakiraman, M., Leliavski, A., Varadarajulu, J., Jenne, D., Krishnamoorthy, G. 2023; 20 (1): 291

  Abstract

  Current effective therapies for autoimmune diseases rely on systemic immunomodulation that broadly affects all T and/or B cell responses. An ideal therapeutic approach would combine autoantigen-specific targeting of both T and B cell effector functions, including efficient removal of pathogenic autoantibodies. Albeit multiple strategies to induce T cell tolerance in an autoantigen-specific manner have been proposed, therapeutic removal of autoantibodies remains a significant challenge. Here, we devised an approach to target both autoantigen-specific T cells and autoantibodies by producing a central nervous system (CNS) autoantigen myelin oligodendrocyte glycoprotein (MOG)-Fc fusion protein. We demonstrate that MOG-Fc fusion protein has significantly higher bioavailability than monomeric MOG and is efficient in clearing anti-MOG autoantibodies from circulation. We also show that MOG-Fc promotes T cell tolerance and protects mice from MOG-induced autoimmune encephalomyelitis. This multipronged targeting approach may be therapeutically advantageous in the treatment of autoimmunity.

  View details for DOI 10.1186/s12974-023-02974-9

  View details for PubMedID 38057803

  View details for PubMedCentralID PMC10702099

• High salt diet does not impact the development of acute myeloid leukemia in mice. Cancer immunology, immunotherapy : CII Janakiraman, M., Salei, N., Krishnamoorthy, G. 2023; 72 (1): 265-273

  Abstract

  The gut microbiota has not only been implicated in the development of some cancers but has also been shown to modulate the efficacy of cancer therapeutics. Although the microbiota is an attractive target in cancer therapy, there is limited data available regarding the relevance of microbiota and dietary interventions in the various types of tumors. Recently, a high salt diet (HSD) has attracted attention in cancer development owing to its profound effects on modulating microbiota and immune responses. Here, we investigated the impact of HSD on microbiota, immune responses, and the development of acute myeloid leukemia using two syngeneic transplantation models. HSD significantly changes the microbiota composition, TH17 responses, and NK cells. However, we found no influence of HSD on tumor development. The kinetics and characteristics of tumor development were similar despite varying the number of injected tumor cells. Our data show that the effects of the microbiome and dietary interventions can be tumor-specific and may not apply to all types of cancers.

  View details for DOI 10.1007/s00262-022-03244-y

  View details for PubMedID 35802166

  View details for PubMedCentralID PMC9813099

• A novel CD4 knockout mouse strain with a spontaneous frameshift mutation in the CD4 locus. PloS one Janakiraman, M., Na, S. Y., Krishnamoorthy, G. 2022; 17 (4): e0266589

  Abstract

  T cells express co-receptors CD4 and CD8, which are involved in the recognition of antigen presented to T cell receptors. The expression of CD4 in thymic hematopoietic cells is crucial for the thymic development and selection of T cells. In this study, we identified a novel CD4 mutant allele that emerged spontaneously in our mouse colony. The frameshift mutation led to a truncated CD4 protein which failed to reach the plasma membrane resulting in impaired development of CD4+ helper T cells. The CRISPR mediated correction of mutant allele restored the membrane CD4 expression. Further, using an adoptive transfer of T cells, we show that this model is an ideal recipient mouse for the study of CD4+ T cells.

  View details for DOI 10.1371/journal.pone.0266589

  View details for PubMedID 35385550

  View details for PubMedCentralID PMC8985997

• Role of microglial and endothelial CD36 in post-ischemic inflammasome activation and interleukin-1β-induced endothelial activation. Brain, behavior, and immunity Garcia-Bonilla, L., Sciortino, R., Shahanoor, Z., Racchumi, G., Janakiraman, M., Montaner, J., Zhou, P., Anrather, J., Iadecola, C. 2021; 95: 489-501

  Abstract

  Cerebral ischemia is associated with an acute inflammatory response that contributes to the resulting injury. The innate immunity receptor CD36, expressed in microglia and endothelium, and the pro-inflammatory cytokine interleukin-1β (IL-1β) are involved in the mechanisms of ischemic injury. Since CD36 has been implicated in activation of the inflammasome, the main source of IL-1β, we investigated whether CD36 mediates brain injury through the inflammasome and IL-1β. We found that active caspase-1, a key inflammasome component, is decreased in microglia of CD36-deficient mice subjected to transient middle cerebral artery occlusion, an effect associated with a reduction in brain IL-1β. Conditional deletion of CD36 either in microglia or endothelium reduced ischemic injury in mice, attesting to the pathogenic involvement of CD36 in both cell types. Application of an ischemic brain extract to primary brain endothelial cell cultures from wild type (WT) mice induced IL-1β-dependent endothelial activation, reflected by increases in the cytokine colony stimulating factor-3, a response markedly attenuated in CD36-deficient endothelia. Similarly, the increase in colony stimulating factor-3 induced by recombinant IL-1β was attenuated in CD36-deficient compared to WT endothelia. We conclude that microglial CD36 is a key determinant of post-ischemic IL-1β production by regulating caspase-1 activity, whereas endothelial CD36 is required for the full expression of the endothelial activation induced by IL-1β. The data identify microglial and endothelial CD36 as critical upstream components of the acute inflammatory response to cerebral ischemia and viable putative therapeutic targets.

  View details for DOI 10.1016/j.bbi.2021.04.010

  View details for PubMedID 33872708

  View details for PubMedCentralID PMC8187325

• High-salt diet suppresses autoimmune demyelination by regulating the blood-brain barrier permeability PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Na, S., Janakiraman, M., Leliavski, A., Krishnamoorthy, G. 2021; 118 (12)

  Abstract

  Sodium chloride, "salt," is an essential component of daily food and vitally contributes to the body's homeostasis. However, excessive salt intake has often been held responsible for numerous health risks associated with the cardiovascular system and kidney. Recent reports linked a high-salt diet (HSD) to the exacerbation of artificially induced central nervous system (CNS) autoimmune pathology through changes in microbiota and enhanced TH17 cell differentiation [M. Kleinewietfeld et al., Nature 496, 518-522 (2013); C. Wu et al., Nature 496, 513-517 (2013); N. Wilck et al., Nature 551, 585-589 (2017)]. However, there is no evidence that dietary salt promotes or worsens a spontaneous autoimmune disease. Here we show that HSD suppresses autoimmune disease development in a mouse model of spontaneous CNS autoimmunity. We found that HSD consumption increased the circulating serum levels of the glucocorticoid hormone corticosterone. Corticosterone enhanced the expression of tight junction molecules on the brain endothelial cells and promoted the tightening of the blood-brain barrier (BBB) thereby controlling the entry of inflammatory T cells into the CNS. Our results demonstrate the multifaceted and potentially beneficial effects of moderately increased salt consumption in CNS autoimmunity.

  View details for DOI 10.1073/pnas.2025944118

  View details for Web of Science ID 000631868600076

  View details for PubMedID 33723078

  View details for PubMedCentralID PMC7999868

• Emerging Role of Diet and Microbiota Interactions in Neuroinflammation. Frontiers in immunology Janakiraman, M., Krishnamoorthy, G. 2018; 9: 2067

  Abstract

  Commensal gut microbiota exerts multifarious effects on intestinal and extra-intestinal immune homeostasis. A disruption in the microbial composition of the gut has been associated with many neurological disorders with inflammatory components. Here we review known associations between gut microbiota and neurological disorders. Further we highlight the emerging role of diet and microbiota interrelationship in regulating neuroinflammation.

  View details for DOI 10.3389/fimmu.2018.02067

  View details for PubMedID 30254641

  View details for PubMedCentralID PMC6141752