Biology subjects

Nistala, R.

Publications and source records attributed to Nistala, R..

3 recordsLinked to original sources

bioRxiv2025

Sphingosine kinase 2 suppresses neutrophil responses to promote viral persistence while attenuating immune pathology

Chronic virus infections often suppress immune cell functions which helps in restricting immune pathology but leads to viral persistence. However, the underlying mechanisms are incompletely understood. We recently found that sphingosine kinase 2 (SphK2)-deficient (Sphk2-/-) mice succumbed to lymphocytic choriomeningitis virus (LCMV) infection due to immune pathology. In addition to heightened T cell immunity, a notable increase of neutrophils was observed in LCMV-infected Sphk2-/- mice. Depletion of neutrophils increased the viability of virus-infected Sphk2-/- mice, supporting a role of SphK2-deficient neutrophils in viral immune pathogenesis. Further, SphK2-deficient neutrophils expressed lower levels of the immune suppressive marker CD244 during infection. Importantly, adoptively transferred SphK2-deficient neutrophils demonstrated intrinsic regulation of CD244 and improved virus-specific T cell responses, resulting in diminished viral burden. Transcriptomic analysis revealed increased expression of pro-inflammatory and antiviral genes in SphK2-deficient neutrophils. These results indicate that SphK2 promotes suppressive neutrophil responses and regulates neutrophil-associated immune pathology during a persistent infection. Our findings may help design new immune therapeutics to control chronic viral diseases. SignificanceNeutrophils are the sentinels of the innate immune system; they can reshape innate and adaptive immune responses. During chronic illnesses, such as persistent viral infections, neutrophils can suppress the host immune response and help in disease progression. Here, we demonstrate regulation of neutrophil expansion and functions by sphingosine kinase 2 (SphK2) during LCMV infection. SphK2-deficient neutrophils express a reduced level of inhibitory receptor CD244, exert immune stimulatory effects on T cells, and promote virus clearance. Further, transcriptomic analysis reveals that SphK2 deficiency leads to the development of proinflammatory neutrophils. Our study identifies SphK2, a host factor, as being critical for neutrophil suppression that regulates dysfunctional T cell response and virus persistence.

immunology↗

bioRxiv2024

Impact of Proximal Tubule-Specific Deletion of Dipeptidyl Peptidase 4 on Blood Pressure, Renal Sodium Handling, and NHE3 Phosphorylation

Dipeptidyl peptidase 4 (DPP4) is a transmembrane serine exopeptidase abundantly expressed in the kidneys, predominantly in the proximal tubule (PT); however, its non-enzymatic functions in this nephron segment remain poorly understood. While DPP4 physically associates with the Na+/H+ exchanger isoform 3 (NHE3) and its inhibitors exert natriuretic effects, the DPP4 role in blood pressure (BP) regulation remains controversial. This study investigated the effects of PT-specific Dpp4 deletion (Dpp4{Delta}PT) and global Dpp4 deletion (Dpp4-/-) on systolic blood pressure (SBP), natriuresis, and NHE3 regulation under baseline and angiotensin II (Ang II)-stimulated conditions in both male and female mice. Global and PT-specific Dpp4 deletion increased diuretic and natriuretic responses to acute saline loading, correlating with enhanced phosphorylation of NHE3 at serine 552 (pS552-NHE3). However, baseline SBP remained unchanged. Ang II stimulation increased DPP4 activity in control mice, with a greater effect in males than in females, reflecting sex-dependent regulation of renal DPP4. In Dpp4{Delta}PT mice, residual kidney DPP4 was unresponsive to Ang II, indicating that PT DPP4, rather than DPP4 in other nephron segments, is regulated by Ang II. Ang II administration increased SBP in all groups; however, the pressor response was significantly attenuated in both Dpp4{Delta}PT and Dpp4-/- mice, coinciding with sustained elevated levels of pS552-NHE3. Collectively, these findings demonstrate that PT DPP4 modulates NHE3 activity through mechanisms that prevent the accumulation of pS552-NHE3, exerting an anti-natriuretic effect. In the absence of DPP4, these mechanisms are disrupted, reducing Ang II sensitivity and maintaining high pS552-NHE3 levels, underscoring the role of DPP4 in PT signaling and function.

physiology↗

bioRxiv2024

Dynamic Localization of Leukemia Stem Cells via CXCL12 Regulates Leukemia Progression

The processes that govern leukemia progression and remission are poorly understood. Our research reveals that the CXCL12 gradient, traditionally associated with LSC quiescence and survival, critically determines LSC localization and associated behavior. Specifically, CXCL12 guides LSCs to either the quiescent niche in the metaphysis, characterized by N-cadherin-expressing mesenchymal stromal cells (N-cad+ MSCs), or the proliferative niche in the central marrow (CM), marked by sinusoidal endothelial cells and associated stromal cells. We identified that the CXCL12 gradient is finely regulated by the interplay between dipeptidyl peptidase 4 (DPP4) on LSCs and glypican-3 (GPC3) on N-cad+ MSCs. DPP4 deactivates CXCL12, while GPC3 inhibits DPP4, resulting in a higher CXCL12 concentration in the metaphysis and a lower concentration in the CM. This differential gradient facilitates leukemia progression by promoting LSC quiescence and survival in the metaphysis versus relative proliferation and apoptosis in the CM. Depletion of Dpp4 from LSCs or Cxcl12 from N-cad+ MSCs disrupts this gradient, mobilizing LSCs from the metaphysis to the CM and significantly hindering leukemia development. Our findings redefine the role of CXCL12 in LSC behavior and provide a clearer understanding of leukemia progression. This novel insight highlights the potential for targeted therapeutic strategies that disrupt the CXCL12 gradient to treat minimal residual LSCs, offering a promising path toward a lasting cure for acute myeloid leukemia (AML).

cancer biology↗