Abdelillah Soussi Gounni

Semaphorins are a large family of proteins originally identified for their roles in axon guidance during neural development. Recent findings have established the importance of semaphorins members in modulating diverse immune responses of T cells in vitro and in vivo. Class 3 semaphorins, typified by Sema3A, signal through Neuropilin-1 and Plexin-A receptors in an activation-dependent manner, suppressing effector proliferation while promoting regulatory T cell stability and shaping cytokine profiles in autoimmunity and cancer. Sema3E and Sema3F similarly fine-tune host defense and inflammation by directing Th1/Th17 responses or restraining aberrant chemotaxis. Class 4 members, such as Sema4A and Sema4D, engage Plexin-B1, Plexin-D1, and CD72 to deliver both “forward” co-stimulatory and “reverse” signals: they amplify CD4⁺ and CD8⁺ effector functions, support T helper-B cell crosstalk, and influence tumor immunity via receptor shedding and bidirectional signaling. Finally, although less well defined, class 7 Sema7A operates indirectly—through APCs and Tregs—to regulate inflammatory recall responses and Th1/Th17 driven pathology. Together, these semaphorin-mediated pathways underscore a complex, context-dependent network that balances protective immunity against immunopathology, offering novel therapeutic targets in autoimmunity, infection, and cancer.

Background: Type 2-low asthma is a severe, steroid-resistant phenotype characterized by neutrophilic inflammation and limited treatment options. PTX3, an acute-phase protein involved in innate immunity, has been linked to inflammatory diseases; but its role in type 2-low asthma remains unclear. Methods: A chronic HDM + c-di-GMP murine model was used to mimic type 2-low asthma. PTX3 ^−/− and WT mice were assessed for inflammation, cytokine profiles, antibody responses, and lung function. AHR was measured using FlexiVent. BALF inflammatory cells were analyzed by cytospin and flow cytometry. Cytokines were quantified using mesoscale assay, and serum immunoglobulins by ELISA. Results: In mice, the type 2-low model exhibited increased systemic and airway PTX3 levels. PTX3 ^−/− mice exposed to the type 2-low protocol developed significantly greater airway inflammation, with higher total BALF cell counts and a 2-fold increase in neutrophils, but no change in eosinophils. PTX3 deficiency led to increased total and HDM-specific IgE levels. BALF cytokine analysis revealed elevated IL-17A in PTX3 ^−/− mice, while IL-4, IL-5, and IL-13 remained unchanged. PTX3 ^−/− mice also exhibited significantly higher AHR parameters. Conclusions: PTX3 absence enhances neutrophilic inflammation, IL-17A production, IgE responses, and AHR, highlighting PTX3 as a potential biomarker and therapeutic target in type 2- low asthma.

Background: Asthma is marked by chronic airway inflammation, immune dysregulation, and airway remodeling. While TSLP is known to influence allergic diseases like asthma, the role of TSLPR in airway remodeling is not well-defined. Methods: Using TSLPR-deficient (TSLPR ^-/- ) mice in a chronic HDM asthma model, we assessed lung function, inflammatory cell infiltration, cytokine levels, and antibody production in serum and lung tissues. Airway remodeling was evaluated by examining mucus production, goblet cell metaplasia, and collagen deposition. Results: TSLPR ^-/- mice showed lower airway resistance, tissue resistance, and tissue elastance compared to wild-type mice after chronic HDM exposure. TSLPR ^-/- mice also had reduced HDM-specific IgE levels and decreased IL-4, IL-13, and IFN-γ in BALF. However, airway and lung inflammation, including inflammatory cell counts and eosinophil infiltration, were similar between TSLPR ^-/- and WT mice. Collagen deposition, mucus production, and goblet cell changes were also comparable. Conclusion: TSLPR deficiency reduced airway hyperresponsiveness but did not significantly impact lung eosinophil and neutrophil counts or mucus and collagen production in a chronic HDM asthma model, highlighting the complex role of TSLP and TSLPR in severe asthma.

Semaphorin3E has shown promise in alleviating the severity of asthma in preclinical studies; however, its role in the chronic features of type 2-low asthma remains unclear. Therefore, we aimed to investigate the role of Sema3E in a mouse model of severe asthma that exhibits a mix of granulocytic inflammation with neutrophils dominance and compared the results with those from the type-2 high eosinophilic asthma model. Sema3E knockout (KO) and wild-type (WT) mice were subjected to type-2 low and type-2 high regimens using house dust mite (HDM) combined with cyclic-di-GMP or HDM alone, respectively. Airway hyperresponsiveness parameters were measured using the FlexiVent ventilator. Bronchoalveolar lavage fluid cell phenotyping was performed by flowcytometry. Additionally, cytokines and antibodies were quantified using Mesoscale and ELISA. Mucus overproduction and goblet cell hyperplasia were visualized by Periodic-acid–Schiff staining. In comparison to WT mice, Sema3E KO mice exhibited an enhanced tissue resistance and tissue elastance in the type 2-low asthma model. Concurrently, Sema3E KO mice that were subjected to the type-2 low asthma model demonstrated an elevated presence of pulmonary neutrophils, dendritic cells, CD4 T cells, as well as increased levels of IL-17, TNF, IL-1β, CXCL-8, and MCP-1/CCL2 in comparison to their WT counterparts. However, in the type-2 high model, Sema3E KO mice exhibited a significant increase in goblet cell numbers and mucus overproduction, as well as enhancements in the number of eosinophils, IgE-producing B cells, and IL-4 levels compared to WT mice, highlighting the homeostatic role of Sema3E in the distinct immune niche of type-2 low and type-2 high asthma. Overall, our data showed that Sema3E is critical in modulating AHR, airway inflammation, and tissue remodelling in type 2 low and type 2 high phenotypes of asthma. The Sema3E regulatory network varies depending on the immunization regimen, affecting distinct parameters in type-2 low and type-2 high asthma models.

Semaphorin3E has shown promise in alleviating the severity of asthma in preclinical studies; however, its role in the chronic features of type 2-low asthma remains unclear. Therefore, we aimed to investigate the role of Sema3E in a mouse model of severe asthma that exhibits a mix of granulocytic inflammation with neutrophils dominance and compared the results with those from the type-2 high eosinophilic asthma model. Sema3E knockout (KO) and wild-type (WT) mice were subjected to type-2 low and type-2 high regimens using house dust mite (HDM) combined with cyclic-di-GMP or HDM alone, respectively. Airway hyperresponsiveness parameters were measured using the FlexiVent ventilator. Bronchoalveolar lavage fluid cell phenotyping was performed by flowcytometry. Additionally, cytokines and antibodies were quantified using Mesoscale and ELISA. Mucus overproduction and goblet cell hyperplasia were visualized by Periodic-acid–Schiff staining. In comparison to WT mice, Sema3E KO mice exhibited an enhanced tissue resistance and tissue elastance in the type 2-low asthma model. Concurrently, Sema3E KO mice that were subjected to the type-2 low asthma model demonstrated an elevated presence of pulmonary neutrophils, dendritic cells, CD4 T cells, as well as increased levels of IL-17, TNF, IL-1β, CXCL-8, and MCP-1/CCL2 in comparison to their WT counterparts. However, in the type-2 high model, Sema3E KO mice exhibited a significant increase in goblet cell numbers and mucus overproduction, as well as enhancements in the number of eosinophils, IgE-producing B cells, and IL-4 levels compared to WT mice, highlighting the homeostatic role of Sema3E in the distinct immune niche of type-2 low and type-2 high asthma. Overall, our data showed that Sema3E is critical in modulating AHR, airway inflammation, and tissue remodelling in type 2 low and type 2 high phenotypes of asthma. The Sema3E regulatory network varies depending on the immunization regimen, affecting distinct parameters in type-2 low and type-2 high asthma models.

Idiopathic pulmonary fibrosis (IPF) is characterized by excessive fibroblast recruitment and persistent extracellular matrix deposition at sites of tissue injury, leading to severe morbidity and mortality. However, the precise mechanisms by which fibroblasts contribute to IPF pathogenesis remain poorly understood. The study reveals that Sema3E and its receptor Plexin D1 are significantly overexpressed in the lungs of IPF patients and bleomycin (BLM)‐induced lung fibrotic mice. Elevated plasma levels of Sema3E in IPF patients are negatively correlated with lung function. Importantly, Sema3E in IPF lungs predominantly exists as the P61‐Sema3E. The knockdown of Sema3E or Plexin D1 effectively inhibits fibroblast activation, proliferation, and migration. Mechanistically, Furin‐mediated cleavage of P87‐Sema3E into P61‐Sema3E drives these pro‐fibrotic activities, with P61‐Sema3E‐PlexinD1 axis promoting fibroblast activation, proliferation, and migration by affecting the phosphorylation of ErbB2, which subsequently activates the ErbB2 pathways. Additionally, Furin inhibition reduces fibroblast activity by decreasing P61‐Sema3E production. In vivo, both whole‐lung Sema3E knockdown and fibroblast‐specific Sema3E knockout confer protection against BLM‐induced lung fibrosis. These findings underscore the crucial role of the P61‐Sema3E‐Plexin D1 axis in IPF pathogenesis and suggest that targeting this pathway may hold promise for the development of novel therapeutic strategies for IPF treatment.

Semaphorin3E (Sema3E), a protein guiding cell movement, is found in various cell types like neural, immune, cancer, and epithelial cells. This study examines Sema3E in chronic obstructive pulmonary disease (COPD) airways. In patients with COPD, airway smooth muscle cells express Sema3E and its receptor PlxD1. Unlike healthy cells, Sema3E does not hinder cell proliferation in COPD, indicating involvement in airway remodeling. These findings highlight the Sema3E-PlxD1 axis in COPD airway changes.

Dendritic cells (DCs) are pivotal in regulating allergic asthma. Our research has shown that the absence of Sema3E worsens asthma symptoms in acute and chronic asthma models. However, the specific role of PlexinD1 in these processes, particularly in DCs, remains unclear. This study investigates the role of PlexinD1 in CD11c+ DCs using a house dust mite (HDM) model of asthma. We generated CD11c+ DC-specific PlexinD1 knockout (CD11c^{PLXND1 KO}) mice and subjected them, alongside wild-type controls (PLXND1^fl/fl), to an HDM allergen protocol. Airway hyperresponsiveness (AHR) was measured using FlexiVent, and immune cell populations were analyzed via flow cytometry. Cytokine levels and immunoglobulin concentrations were assessed using mesoscale and ELISA, while collagen deposition and mucus production were examined through Sirius-red and periodic acid Schiff (PAS) staining respectively. Our results indicate that CD11c^{PLXND1 KO} mice exhibit significantly exacerbated AHR, characterized by increased airway resistance and tissue elastance. Enhanced mucus production and collagen gene expression were observed in these mice compared to wild-type counterparts. Flow cytometry revealed higher CD11c+ MHCII^high CD11b+ cell recruitment into the lungs, and elevated total and HDM-specific serum IgE levels in CD11c^{PLXND1 KO} mice. Mechanistically, co-cultures of B cells with DCs from CD11c^{PLXND1 KO} mice showed significantly increased IgE production compared to wild-type mice.These findings highlight the critical regulatory role of the plexinD1 signaling pathway in CD11c+ DCs in modulating asthma features.

Dendritic cells (DC) play a crucial role in regulating allergic asthma. We have demonstrated that the absence of semaphorin3E (Sema3E) exacerbates asthma features in acute and chronic asthma models. However, the role of plexinD1 in these events, especially in DC is unknown. Therefore, we investigated the role of plexinD1 in CD11c+ DC in the HDM model of asthma. CD11c+ DC-specific plexinD1 knockout mice and wild-type mice were subjected to HDM acute allergen protocol. Airway hyperresponsiveness (AHR) parameters were measured using the FlexiVent ventilator. Lung tissue and bronchoalveolar lavage fluid (BALF) were processed by flow cytometry. Cytokines and antibodies were measured using mesoscale and ELISA. Collagen deposition and mucus production were visualized by histological staining, and associated genes were investigated using Real-time PCR. We showed that DC-specific plexinD1 knockout mice exhibited exacerbated airway hyperresponsiveness, including increased airway resistance and tissue elastance. These mice displayed enhanced levels of mucus production and collagen gene expression compared to wild-type mice. These events were accompanied by enhanced recruitment of conventional DCs, specifically CD11b+ cDC2, into the lungs and higher levels of total and HDM-specific serum IgE in CD11c ^{PLXND1 KO} compared to wild-type counterparts. Mechanistically, a significantly higher level of IgE in the co-culture of B-DCs isolated from CD11c ^{PLXND1 KO} mice compared to DCs isolated from wild-type mice. Overall, our data reveals that the Sema3E-plexinD1 signalling pathway in CD11c+ DC is critical in modulating asthma features. Graphical