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Cish knockout mice exhibit similar outcomes to malaria infection despite altered hematopoietic responses.

ABSTRACT: The Cytokine-inducible Src homology 2 domain-containing (CISH) protein is a negative feedback regulator induced by cytokines that play key roles in immunity and erythropoiesis. Single nucleotide polymorphisms (SNPs) in the human CISH gene have been associated with increased susceptibility to severe malaria disease. To directly assess how CISH might influence outcomes in the BALB/c model of malaria anemia, CISH knockout (Cish^-/-) mice on this background were infected with Plasmodium berghei and their hematopoietic responses, cytokine production and ability to succumb to severe malaria disease evaluated. Despite basal erythrocytic disruption, upon P. berghei infection, the Cish ^-/- mice were better able to maintain peripheral blood cell counts, hemoglobin levels and a steady-state pattern of erythroid differentiation compared to wild-type (Cish^+/+) mice. Ablation of CISH, however, did not influence the outcome of acute malaria infections in either the BALB/c model or the alternative C57BL/6 model of experimental cerebral malaria, with the kinetics of infection, parasite load, weight loss and cytokine responses being similar between Cish^+/+ and Cish^-/- mice, and both genotypes succumbed to experimental cerebral malaria within a comparable timeframe.

SUBMITTER: Lakkavaram AL

PROVIDER: S-EPMC10653303 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Cish knockout mice exhibit similar outcomes to malaria infection despite altered hematopoietic responses.

Lakkavaram Asha L AL Maymand Saeed S Naser Wasan W Ward Alister C AC de Koning-Ward Tania F TF

Frontiers in microbiology 20231102

The Cytokine-inducible Src homology 2 domain-containing (CISH) protein is a negative feedback regulator induced by cytokines that play key roles in immunity and erythropoiesis. Single nucleotide polymorphisms (SNPs) in the human CISH gene have been associated with increased susceptibility to severe malaria disease. To directly assess how CISH might influence outcomes in the BALB/c model of malaria anemia, CISH knockout (Cish-/-) mice on this background were infected with ...[more]

PMID: 38029163

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Project description:Skeletal muscle regrowth after atrophy is impaired in the aged and in this study we hypothesized that this can be explained by a blunted response of signaling pathways and cellular processes during reloading after hind limb suspension in muscles from old rats. Male Brown Norway Fisher 344 rats at 6 (young) and 32 (old) months of age were subjected to normal ambulatory conditions (amb), hind limb suspension for 14 days (HS), and HS followed by reloading through normal ambulation for 14 days (RE); soleus muscles were used for analysis of intracellular signaling pathways and cellular processes. Soleus muscle regrowth was blunted in old compared to young rats which coincided with a recovery of serum IGF-1 and IGFBP-3 levels in young but not old. However, the response to reloading for p-Akt, p-p70s6k and p-GSK3β protein abundance was similar between muscles from young and old rats, even though main effects for age indicate an increase in activation of this protein synthesis pathway in the aged. Similarly, MAFbx mRNA levels in soleus muscle from old rats recovered to the same extent as in the young, while Murf-1 was unchanged. mRNA abundance of autophagy markers Atg5 and Atg7 showed an identical response in muscle from old compared to young rats, but beclin did not. Autophagic flux was not changed at either age at the measured time point. Apoptosis was elevated in soleus muscle from old rats particularly with HS, but recovered in HSRE and these changes were not associated with differences in caspase-3, -8 or -9 activity in any group. Protein abundance of apoptosis repressor with caspase-recruitment domain (ARC), cytosolic EndoG, as well as cytosolic and nuclear apoptosis inducing factor (AIF) were lower in muscle from old rats, and there was no age-related difference in the response to atrophy or regrowth. Soleus muscles from old rats had a higher number of ED2 positive macrophages in all groups and these decreased with HS, but recovered in HSRE in the old, while no changes were observed in the young. Pro-inflammatory cytokines in serum did not show a differential response with age to different loading conditions. Results indicate that at the measured time point the impaired skeletal muscle regrowth after atrophy in aged animals is not associated with a general lack of responsiveness to changes in loading conditions.

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Cish knockout mice exhibit similar outcomes to malaria infection despite altered hematopoietic responses.

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<i>Cish</i> knockout mice exhibit similar outcomes to malaria infection despite altered hematopoietic responses.

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