Kanti et al. report that adipose triglyceride lipase, the rate-limiting enzyme for intracellular lipolysis, is critical for club cell–driven regeneration of bronchiolar epithelia in mice. In the cover image, an electron micrograph of an Atgl-KO/cTg club cell shows substantial lipid accumulation within the intracellular lipid droplets.
Understanding the reorganization of neural circuits spared after spinal cord injury in the motor cortex and spinal cord would provide insight for developing therapeutics. Using optogenetic mapping we demonstrate a transhemispheric recruitment of neural circuits in the contralateral cortical M1/M2 area to improve the impaired forelimb function after a cervical 5 right-sided hemisection in mice, a model mimicking the human Brown-Séquard syndrome. This cortical reorganization can be elicited by a selective cortical optogenetic neuromodulation paradigm. Areas of whisker, jaw, and neck, together with the rostral forelimb area, on the motor cortex ipsilateral to the lesion are engaged to control the ipsilesional forelimb in both stimulation and non-stimulation groups at 8 weeks post-injury. However, significant functional benefits are only seen in the stimulation group. Using anterograde tracer, we further reveal a robust sprouting of the intact corticospinal tract in the spinal cord of those animals receiving optogenetic stimulation. The intraspinal cortical spinal axonal sprouting corelates with the forelimb functional recovery. Thus, specific neuromodulation of the cortical neural circuits induces massive neural reorganization both in the motor cortex and spinal cord, constructing an alternative motor pathway in restoring impaired forelimb function.
Wei Wu, Tyler Nguyen, Josue D. Ordaz, Yi Ping Zhang, Nai-Kui Liu, Xinhua Hu, Yuxiang Liu, Xingjie Ping, Qi Han, Xiangbing Wu, Wenrui Qu, Sujuan Gao, Christopher B. Shields, Xiaoming Jin, Xiao-Ming Xu
Tertiary lymphoid structures (TLSs) are transient ectopic lymphoid aggregates whose formation might be caused by chronic inflammation states, such as cancer. However, how TLSs are induced in the tumor microenvironment (TME) and how they affect patient survival are not well understood. We investigated TLS distribution in relation to tumor infiltrating lymphocytes (TILs) and related gene expression in high grade serous ovarian cancer (HGSC) specimens. CXCL13 gene expression correlated with TLS presence and the infiltration of T cells and B cells, and was a favorable prognostic factor for HGSC patients. Coexistence of CD8+ T cells and B-cell lineages in the TME significantly improved the prognosis of HGSC and was correlated with the presence of TLSs. CXCL13 expression was predominantly coincident with CD4+ T cells in TLSs and CD8+ T cells in TILs, and shifted from CD4+ T cells to CD21+ follicular dendritic cells as TLS matured. In a mouse ovarian cancer model, recombinant CXCL13 induced TLSs and enhanced survival by the infiltration of CD8+ T cells. These results suggest that TLS formation was associated with CXCL13-producing CD4+ T cells and that TLSs facilitated the coordinated antitumor response of cellular and humoral immunity in ovarian cancer.
Masayo Ukita, Junzo Hamanishi, Hiroyuki Yoshitomi, Koji Yamanoi, Shiro Takamatsu, Akihiko Ueda, Haruka Suzuki, Yuko Hosoe, Yoko Furutake, Mana Taki, Kaoru Abiko, Ken Yamaguchi, Hidekatsu Nakai, Tsukasa Baba, Noriomi Matsumura, Akihiko Yoshizawa, Hideki Ueno, Masaki Mandai
Nontuberculous mycobacteria (NTM) are an increasingly common cause of respiratory infection in people with cystic fibrosis (PwCF). Relative to those with no history of NTM infection (CF-NTMNEG), PwCF and a history of NTM infection (CF-NTMPOS) are more likely to develop severe lung disease and experience complications over the course of treatment. In other mycobacterial infections (e.g. tuberculosis), an overexuberant immune response causes pathology and compromises organ function; however, since the immune profiles of CF-NTMPOS and CF-NTMNEG airways are largely unexplored, it is unknown which if any immune responses distinguish these cohorts or concentrate in damaged tissues. Here we evaluated lung lobe-specific immune profiles of three cohorts (CF-NTMPOS, CF-NTMNEG, and non-CF adults) and found that CF-NTMPOS airways are distinguished by a hyper-inflammatory cytokine profile. Importantly, the CF-NTMPOS airway immune profile was dominated by B cells, classical macrophages and the cytokines which support their accumulation. These and other immunological differences between cohorts, including the near absence of NK cells and complement pathway members, were enriched in the most damaged lung lobes. The implications of these findings for our understanding of lung disease in PwCF are discussed, as are how they may inform the development of host-directed therapies to improve NTM disease treatment.
Don Hayes, Jr., Rajni Kant Shukla, Yizi Cheng, Emrah Gecili, Marlena R. Merling, Rhonda D. Szczesniak, Assem G Ziady, Jason C. Woods, Luanne Hall-Stoodley, Namal P.M. Liyanage, Richard T. Robinson
We have previously demonstrated that active immunization with the apolipoprotein B-100 (ApoB-100) peptide P210 reduces experimental atherosclerosis. To advance this immunization strategy to future clinical testing, we explored the possibility of delivering P210 as an antigen using nanoparticles, given this approach has now been used clinically. To that end, we first charactered the responses of T cells to P210 using PBMCs from human subjects with atherosclerotic cardiovascular disease (ASCVD). We then investigated the use of P210 in self-assembling peptide amphiphile micelles (P210-PAM) as a vaccine formulation to reduce atherosclerosis in ApoE-/- mice and its potential mechanisms of action. We also generated and characterized a humanized mouse model with chimeric HLA-A*02:01/Kb in ApoE-/- background to test the efficacy of P210-PAM immunization as a bridge for future clinical testing. P210 provoked T cell activation and memory response in PBMCs of human subjects with ASCVD. Dendritic cell uptake of P210-PAM and its co-staining with MHC-I molecules supported its use as a vaccine formulation. In ApoE-/- mice, immunization with P210-PAM dampened P210-specific CD4+ T cell proliferative response and CD8+ T cell cytolytic response, modulated macrophage phenotype, and significantly reduced aortic atherosclerosis. Potential clinical relevance of P210-PAM immunization was demonstrated by reduced atherosclerosis in the humanized ApoE-/- mouse model expressing chimeric HLA-A*02:01/Kb. Taken together, our data supports the experimental and translational use of P210-PAM as a potential vaccine candidate against human ASCVD.
Kuang-Yuh Chyu, Xiaoning Zhao, Jianchang Zhou, Paul C. Dimayuga, Nicole W.M. Lio, Bojan Cercek, Noah T. Trac, Eun Ji Chung, Prediman K. Shah
Rearrangements that drive ectopic MEF2C expression have recurrently been found in human early thymocyte progenitor acute lymphoblastic leukemia (ETP-ALL) patients. Here we show high levels of MEF2C expression in ETP-ALL patients. Using both in vivo and in vitro models of ETP-ALL, we demonstrate that elevated MEF2C expression blocks NOTCH-induced T cell differentiation while promoting a B-lineage program. MEF2C activates a B cell transcriptional program in addition to RUNX1, GATA3 and LMO2, upregulates the IL7R and boosts cell survival by upregulation of BCL2. MEF2C and the Notch pathway therefore demarcate opposite regulators of B- or T-lineage choices, respectively. Enforced MEF2C expression in mouse or human progenitor cells effectively blocks early T cell differentiation and promotes the development of bi-phenotypic lymphoid tumors that co-express CD3 and CD19, resembling human mixed phenotype acute leukemia (MPAL). SIK inhibitors impair MEF2C activity and alleviate the T cell development block. Importantly, this sensitizes cells to prednisolone treatment. Therefore, SIK inhibiting compounds such as dasatinib are potentially a valuable addition to standard chemotherapy for human ETP-ALL.
Kirsten Canté-Barrett, Mariska T. Meijer, Valentina Cordo', Rico Hagelaar, Wentao Yang, Jiyang Yu, Willem K. Smits, Marloes E. Nulle, Joris P. Jansen, Rob Pieters, Jun J. Yang, Jody J. Haigh, Steven Goossens, Jules P.P. Meijerink
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