• Gene Information: Human IL11 gene locates on chromosome 19, encoding a secretory cytokine; IL11RA gene on 9 encodes its specific receptor subunit. Both genes upregulate under inflammatory stimuli to mediate tissue remodeling and type 2 immune responses in respiratory tracts.
• Protein Expression: IL-11 protein is secreted by lung fibroblasts, epithelial cells and smooth muscle cells. IL11RA protein is mainly expressed on airway epithelium, eosinophils and myofibroblasts to capture circulating IL-11 and transduce downstream pathological signals
• Signaling Pathway: IL-11 binding to IL11RA recruits gp130 co-receptor, triggering JAK phosphorylation and STAT3 nuclear translocation. This cascade initiates and amplifies type 2 inflammation, mucus hypersecretion and irreversible airway structural remodeling.
• Therapeutic Inhibition: Neutralizing antibodies against IL-11 or IL11RA block receptor-ligand interaction to inhibit STAT3 activation. Such biologics reduce eosinophil infiltration, mucus overproduction and airway hyperresponsiveness for treating respiratory diseases.

IL11

• The exons 1~5 of mouse Il11 gene that  encode the full-length protein were replaced by human IL11 exons 1~5 in B-hIL11 mice.
• The endogenous mouse promoter, 5′ UTR, and 3′ UTR regions are retained, allowing human IL11 expression to be driven by the mouse Il11 promoter, while endogenous mouse Il11 transcription and translation are abolished.

IL11RA

• The exons 3-11 of mouse Il11ra1 gene that encode the extracellular domain were replaced by human IL11RA exons 3-11 in B-hIL11RA mice.
• The endogenous mouse promoter, 5′ UTR, and 3′ UTR regions are retained, allowing human IL11RA expression to be driven by the mouse Il11ra promoter, while endogenous mouse Il11ra transcription and translation are abolished.

B-hIL11/hIL11RA mice were obtained by crossing B-hIL11 mice and B-hIL11RA mice

• (A) Human IL11 mRNA was exclusively detectable in homozygous B-hIL11 mice but not in wild-type mice.
• (B) Human IL11RA mRNA was exclusively detectable in homozygous B-hIL11RA mice but not in wild-type mice.
• Human IL11 and IL11RA sequences were confirmed via Sanger-Sequencing.

Strain specific analysis of IL11 and IL11RA mRNA expression in wild-type C57BL/6 mice and homozygous humanized B-hIL11 mice and B-hIL11RA mice by RT-PCR. (A) Testis RNA was isolated from wild-type C57BL/6 mice (+/+) and homozygous B-hIL11 mice (H/H), and then cDNA libraries were synthesized by reverse transcription, followed by PCR with human IL11 primers. (B) Liver RNA was isolated from wild-type C57BL/6 mice (+/+) and homozygous B-hIL11RA mice (H/H), and then cDNA libraries were synthesized by reverse transcription, followed by PCR with human IL11RA primers.

• Mouse IL11 was only detectable in wild-type C57BL/6 mice but not in homozygous B-hIL11/hIL11RA mice. 
• Human IL11 was exclusively detectable in homozygous B-hIL11/hIL11RA mice.

Strain specific IL11 expression analysis in homozygous B-hIL11/hIL11RA mice by ELISA. Wild-type C57BL/6 mice (+/+) and homozygous B-hIL11/hIL11RA mice (H/H) (female, 7 week-old, n=5) were fasted overnight and induced with APAP (400 mg/kg) for 24 h. Then Serum was collected and analyzed by ELISA with species-specific IL11 ELISA kit (mouse IL11: abcam, ab215084; human IL11:R&D, D1100).

• IL11RA was detectable in wild-type C57BL/6 mice and homozygous B-hIL11/hIL11RA mice, as the antibody was cross-reactive between human and mouse. 

Protein expression analysis of IL11RA in homozygous B-hIL11/hIL11RA mice. Various tissue lysates were collected from wild-type C57BL/6 mice (+/+) and homozygous B-hIL11/hIL11RA mice (H/H), and then analyzed by western blot with anti-IL11RA antibody (abcam, ab125015).

• Positive shift of fluorescence signal was observed using anti-IL11RA antibodies relative to isotype control, demonstrating robust target-binding capacity of the anti-IL11RA antibodies.

Antibody binding detection in homozygous B-hIL11RA mice by flow cytometry. Liver was collected from wild-type C57BL/6 mice (+/+) and homozygous B-hIL11RA mice (H/H), and analyzed by flow cytometry with anti-IL11RA antibodies (Ab1 and Ab2, provided by client). (A) Nonparenchymal cells. (B) Parenchymal cells.

• p-ERK increased after APAP induction in B-hIL11/hIL11RA mice, and the increase degree was similar to that of wild-type C57BL/6 mice.

Functional analysis in APAP-induced liver damage in male B-hIL11/hIL11RA mice. (A) Schematic showing the process of APAP-induced liver damage in B-hIL11/hIL11RA mice. B-hIL11/hIL11RA mice (male, 8 weeks, n=5) were fasted overnight and inducted with APAP (400 mg/kg) for 24 h. Liver tissues were collected for functional analysis. (B) Representative IHC images of liver (200 X). (C) Quantification of ERK and p-ERK positive cells from hepatocytes. Values are expressed as mean ± SD. *p<0.05.

• Humanization of IL11 and IL11RA does not alter hematological parameters.

Values are expressed as mean ± SD.

• Humanization of IL11 and IL11RA does not alter hematological parameters.

Values are expressed as mean ± SD.

• Humanization of IL11 and IL11RA does not alter blood chemistry parameters.

Values are expressed as mean ± SD.

• Humanization of IL11 and IL11RA does not alter blood chemistry parameters.

Values are expressed as mean ± SD.

• No abnormal pathological findings were observed in all tissues examined in 2-month-old B-hIL11/hIL11RA mice (female).

Histopathological analysis of major organs from homozygous B-hIL11/hIL11RA mice. Tissues were collected from B-hIL11/hIL11RA mice (female, 2-month-old, n=3), fixed in 4% paraformaldehyde and stained with hematoxylin and eosin (H&E). Representative photomicrographs are shown. Scale bar: 200x.

• No abnormal pathological findings were observed in all tissues examined in 2-month-old B-hIL11/hIL11RA mice (male).

Histopathological analysis of major organs from homozygous B-hIL11/hIL11RA mice. Tissues were collected from B-hIL11/hIL11RA mice (male, 2-month-old, n=3), fixed in 4% paraformaldehyde and stained with hematoxylin and eosin (H&E). Representative photomicrographs are shown. Scale bar: 200x.

• No abnormal pathological findings were observed in all tissues examined in 12-month-old B-hIL11/hIL11RA mice (female).

Histopathological analysis of major organs from homozygous B-hIL11/hIL11RA mice. Tissues were collected from B-hIL11/hIL11RA mice (female, 12-month-old, n=3), fixed in 4% paraformaldehyde and stained with hematoxylin and eosin (H&E). Representative photomicrographs are shown. Scale bar: 200x.

• No abnormal pathological findings were observed in all tissues examined in 12-month-old B-hIL11/hIL11RA mice (male).

Histopathological analysis of major organs from homozygous B-hIL11/hIL11RA mice. Tissues were collected from B-hIL11/hIL11RA mice (male, 12-month-old, n=3), fixed in 4% paraformaldehyde and stained with hematoxylin and eosin (H&E). Representative photomicrographs are shown. Scale bar: 200x.

• Anti‑hIL11RA antibody treatment decreased F4/80⁺ cells and α‑SMA⁺ areas versus model group G2, demonstrating its efficacy in alleviating liver injury in B‑hIL11/hIL11RA mice.

Anti-human IL11RA antibody inhibited the liver damage in B-hIL11/hIL11RA mice. (A) Schematic of treatment workflow for B-hIL11/hIL11RA mice. Mice (n=8/group) were randomized to standard diet (STD) or HFMCD for 6 weeks; anti-hIL11RA antibody administration began 1 week post-diet initiation, followed by liver tissue harvest for detection.(B, C) Compared with STD group (G1), HFMCD model group (G2) exhibited elevated liver injury markers, increased F4/80⁺ macrophages and α-SMA⁺ areas, confirming successful NASH modeling in B-hIL11/hIL11RA mice (200 X). Data presented as mean ± SEM. HFMCD: high-fat methionine-choline-deficient diet.