Sclerostin Deficiency Alters Peripheral B Lymphocyte Responses in Mice

Chow, A.; Mason, J.; Coney, L.; Bajwa, J.; Zaslavsky, A.; Pellman, Y.; Garcia-Ojeda, M. E.; Economides, A.; Loots, G.; Manilay, J. O.

doi:10.1101/357772

bioRxiv · 10.1101/357772

Sclerostin Deficiency Alters Peripheral B Lymphocyte Responses in Mice

Chow, A.·Mason, J.·Coney, L.·Bajwa, J.·Zaslavsky, A.·Pellman, Y.·Garcia-Ojeda, M. E.·Economides, A.·Loots, G.·Manilay, J. O.

View original source ↗Export metadata ↓

Abstract

Understanding how changes in bone physiology and homeostasis affect immune responses will inform how to retain strong immunity in patients with bone disease and in aged individuals. We previously identified sclerostin (Sost) as a mediator of cell communication between the skeletal and the immune system. Elevated bone mineral density in Sost-knockout (Sost-/-) mice contributes to an altered bone marrow microenvironment and adversely affects B cell development. B cells originate from hematopoietic stem cells within the bone marrow and mature in peripheral lymphoid organs to produce antibodies in response to infection and/or vaccination. In this study, we investigated whether the aberrant B cell development observed in the bone marrow of Sost-/- mice extends to peripheral B cells in the spleen during immune challenge, and if these changes were age-dependent. Concomitant with more severe changes in bone architecture, B cell development in the bone marrow and in the spleen worsened with age in Sost-/- mice. B cell responses to T-independent antigens were enhanced in young Sost-/- mice, whereas responses to T-dependent antigens were impaired. Our results support the hypothesis that the adverse effects of B cell development in the Sost-deficient bone marrow microenvironment extends to the peripheral B cell immune response to protein antigens, and suggest that the B cell response to routine vaccinations should be monitored regularly in patients being treated with sclerostin antibody therapy. In addition, our results open the possibility that Sost regulates the T-independent B cell response, which might be applicable to the improvement of vaccines towards non-protein antigens.

Explore related subjects

immunology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Chow, A., Mason, J., Coney, L., Bajwa, J., Zaslavsky, A., Pellman, Y., Garcia-Ojeda, M. E., Economides, A., Loots, G., Manilay, J. O.. 2018-06-28. Sclerostin Deficiency Alters Peripheral B Lymphocyte Responses in Mice. https://doi.org/10.1101/357772

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Impact of RNA modification and IL-12 boosts on mRNA-LNP vaccine-elicited CD8+ T cell responses

Development of effective HIV-1 vaccines requires strategies for inducing both CD8+ T cell and neutralizing antibody responses. Nucleoside-modified mRNA-lipid-nanoparticles (LNP) induce more potent antibody responses than unmodified mRNA-LNP vaccines, while unmodified mRNA is typically employed for CD8+ T cell-inducing vaccines. Here, we compared the abilities of differing ratios of unmodified versus modified mRNA expressing a SIV conserved-region CD8+ T cell immunogen co-administered with IL-12-encoding mRNA-LNP during boosting to induce CD8+ T cell and humoral responses in non-human primates, assessing responses in ChAdOx1-primed controls in parallel. Serial priming and boosting with fully-unmodified mRNA elicited higher-magnitude, more CD8-biased T cell responses than fully-modified mRNA, that were durably maintained after the IL-12-encoding mRNA boosts. Inclusion of 30% nucleoside-modified mRNA enhanced antibody titers, suggesting potential benefits to a mixed-composition vaccine.

immunology↗

bioRxiv2026

Oleic acid suppresses NLRP3 inflammasome activation to prevent dermal macrophage death and limit imiquimod-induced psoriasis

Psoriasis is associated with altered lipid metabolism, including reduced expression of fatty acid metabolism genes and decreased circulating oleic acid. Here we report that oral oleic acid supplementation normalized serum oleic acid levels and protected from skin thickening and epidermal hyperplasia in a imiquimod mice model of psoriasis. These effects were associated with preserved skin-resident macrophage numbers and reduced expression of key psoriasis-associated inflammatory markers. Mechanistically, imiquimod induces dermal macrophage death via NLRP3/caspase-1 inflammasome activation, while adoptive transfer of dermal macrophages attenuates psoriasiform inflammation. Oleic acid rescued macrophages from imiquimod and nigericin-induced death in vitro by suppressing NF-{kappa}B and NLRP3/caspase-1 signaling, lowering IL-1{beta} and reactive oxygen species production, and restoring mitochondrial homeostasis, independently of TLR7. Together, our results position dermal macrophage survival as a previously unrecognized checkpoint in psoriasiform inflammation, and suggest that restoring lipid metabolic fitness, rather than solely targeting downstream inflammatory mediators, may offer an additional mechanism-based strategy to limit tissue- damaging inflammation.

immunology↗

bioRxiv2026

Pathogenicity of autoreactive TH17 cells is modulated by the TRPM7 kinase

The melastatin-like transient receptor potential channel, TRPM7, is crucial for signaling in leukocytes. It harbors a channel domain, permeable to divalent cations as well as a serine/threonine -kinase, phosphorylating inter alia SMAD2. TRPM7 kinase activity is essential for the differentiation of non-pathogenic T helper 17 (TH17) cells as well as for T cell colonization and alloreactivity in the gut. As pathogenic TH17 (pTH17) cells drive autoimmune diseases, we studied TRPM7 kinase involvement in pTH17 polarization and function as well as in the development of multiple sclerosis (MS), using human T cells and established murine experimental autoimmune encephalomyelitis (EAE) models. Our results reveal an elevated TRPM7 activity in T effector cells derived from the cerebrospinal fluid (CSF) of MS patients, in line with higher functional TRPM7 expression on human TH17 cells. Utilizing a mouse line with disrupted kinase activity (Trpm7R/R), we uncovered both impaired differentiation of pathogenic TH17 cells as well as a significantly milder course of TH17-mediated transfer EAE in Trpm7R/R mice compared to Trpm7+/+ controls. In the CNS of Trpm7R/R mice, the number of FOXP3+ T cells (Tregs) was increased, while fewer TH17 cells infiltrated the CNS due to a migration defect of transferred pTH17 cells in the Trpm7R/R hosts and a failure to reactivate in the intestine, due to reduced MHCII signaling. Thus, inactivation of TRPM7 kinase may represent a promising therapeutic strategy targeting both differentiation and reactivation of pTH17 cells while preserving Tregs function and thereby dampening CNS inflammation in MS.

immunology↗